rs149787233

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001289808.2(CRYAB):c.116C>T(p.Pro39Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000189 in 1,612,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P39Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

CRYAB
NM_001289808.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:3

Conservation

PhyloP100: 6.14

Publications

8 publications found

Variant links:

Genes affected

CRYAB (HGNC:2389): (crystallin alpha B) Mammalian lens crystallins are divided into alpha, beta, and gamma families. Alpha crystallins are composed of two gene products: alpha-A and alpha-B, for acidic and basic, respectively. Alpha crystallins can be induced by heat shock and are members of the small heat shock protein (HSP20) family. They act as molecular chaperones although they do not renature proteins and release them in the fashion of a true chaperone; instead they hold them in large soluble aggregates. These heterogeneous aggregates consist of 30-40 subunits; the alpha-A and alpha-B subunits have a 3:1 ratio, respectively. Two additional functions of alpha crystallins are an autokinase activity and participation in the intracellular architecture. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Alpha-A and alpha-B gene products are differentially expressed; alpha-A is preferentially restricted to the lens and alpha-B is expressed widely in many tissues and organs. Elevated expression of alpha-B crystallin occurs in many neurological diseases; a missense mutation cosegregated in a family with a desmin-related myopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2019]

CRYAB Gene-Disease associations (from GenCC):

myofibrillar myopathy 2
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
cataract 16 multiple types
Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
fatal infantile hypertonic myofibrillar myopathy
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet
early-onset lamellar cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset nuclear cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset posterior polar cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy 1II
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

CRYAB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYAB	NM_001289808.2 link	c.116C>T	p.Pro39Leu	missense_variant	Exon 1 of 3	ENST00000650687.2	NP_001276737.1	P02511V9HW27
CRYAB	NM_001289807.1 link	c.116C>T	p.Pro39Leu	missense_variant	Exon 2 of 4		NP_001276736.1	P02511V9HW27
CRYAB	NM_001368245.1 link	c.116C>T	p.Pro39Leu	missense_variant	Exon 2 of 4		NP_001355174.1
CRYAB	NM_001885.3 link	c.116C>T	p.Pro39Leu	missense_variant	Exon 2 of 4		NP_001876.1	P02511V9HW27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYAB	ENST00000650687.2 link	c.116C>T	p.Pro39Leu	missense_variant	Exon 1 of 3		NM_001289808.2	ENSP00000499082.1		P02511

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000242

AC:

AN:

248140

AF XY:

0.000216

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000401

Gnomad EAS exome

AF:

0.0000548

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000472

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000190

AC:

277

AN:

1460788

Hom.:

Cov.:

AF XY:

0.000204

AC XY:

148

AN XY:

726544

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44566

Ashkenazi Jewish (ASJ)

AF:

0.000383

AC:

AN:

26088

East Asian (EAS)

AF:

0.000101

AC:

AN:

39678

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85874

European-Finnish (FIN)

AF:

0.0000563

AC:

AN:

53322

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000222

AC:

247

AN:

1111664

Other (OTH)

AF:

0.000182

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000184

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41410

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000384

Hom.:

Bravo

AF:

0.000110

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000272

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:3

Jul 01, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 12, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Pro39Leu variant in CRYAB has not been reported in individuals with cardiomy opathy, but has been identified in 5/8594 European American chromosomes by the N HLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1497872 33). Computational analyses (biochemical amino acid properties, conservation, Al ignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an im pact to the protein. Additional information is needed to fully assess the clinic al significance of this variant. -

Mar 17, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CRYAB c.116C>T (p.Pro39Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 248140 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CRYAB causing Cataract 16 Multiple Types, allowing no conclusion about variant significance. c.116C>T has been reported in the presumed heterozygous state in the literature or in unpublished abstracts (Stoevring_2006) in individuals affected with left ventricular noncompaction or hypertrophic cardiomyopathy (example, Miszalski-Jamka_2017). These report(s) do not provide unequivocal conclusions about association of the variant with CRYAB-related conditions. At least one publication reports experimental evidence evaluating an impact on protein function in vitro, however, does not allow convincing conclusions about the variant effect (example, Barati_2024). The following publications have been ascertained in the context of this evaluation (PMID: 38548822, 28798025). ClinVar contains an entry for this variant (Variation ID: 178013). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:3

Mar 10, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Previously reported in an individual with left ventricular non-compaction who also harbored variants in the LMNA and MYLK2 genes (Miszalski-Jamka et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28798025, 32420686) -

Mar 21, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 23, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1II

Uncertain:2

Oct 30, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 39 of the CRYAB protein (p.Pro39Leu). This variant is present in population databases (rs149787233, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with CRYAB-related conditions. ClinVar contains an entry for this variant (Variation ID: 178013). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Myofibrillar myopathy 2;C3554649:Dilated cardiomyopathy 1II;C3808377:Cataract 16 multiple types;C5190691:Fatal infantile hypertonic myofibrillar myopathy

Uncertain:2

Jan 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 20, 2022

Clinical Genomics Laboratory, Stanford Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Pro39Leu variant in the CRYAB gene has been previously reported in 1 individual with LVNC who carried a disease-causing variant in a different gene (Miszalski-Jamka et al., 2017). This variant has also been identified in 70/127,652 European (non-Finnish) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is present in ClinVar (VCV000178013.29). Computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Pro39Leu variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PP3] -

Fatal infantile hypertonic myofibrillar myopathy

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Myofibrillar myopathy 2

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiovascular phenotype

Benign:1

Dec 27, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Cataract 16 multiple types

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

D;D;D;D;D;D;T;T;T;D;D

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

.;D;.;.;.;.;.;D;D;D;.

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.70

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.64

MutationAssessor

Benign

1.9

L;L;L;L;L;L;.;.;.;.;.

PhyloP100

6.1

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.4

N;.;N;N;N;N;N;D;D;D;D

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0020

D;.;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.015

D;D;D;D;D;D;.;.;D;.;.

Polyphen

1.0

D;D;D;D;D;D;.;.;D;.;.

Vest4

0.20

MVP

0.98

MPC

0.91

ClinPred

0.62

GERP RS

5.1

PromoterAI

0.0074

Neutral

(source)

Varity_R

0.91

gMVP

0.61

Mutation Taster

=55/45

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs149787233

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over