rs397516686

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

The NM_001289808.2(CRYAB):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,581,302 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 1 hom. )

Consequence

CRYAB
NM_001289808.2 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:3

Conservation

PhyloP100: 7.67

Publications

6 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: Likely_pathogenic. The variant received 9 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 10 pathogenic variants. Next in-frame start position is after 68 codons. Genomic position: 111910449. Lost 0.383 part of the original CDS.

PP5

Variant 11-111911722-C-T is Pathogenic according to our data. Variant chr11-111911722-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44236.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CRYAB	NM_001289808.2 link	c.3G>A	p.Met1?	start_lost	Exon 1 of 3	ENST00000650687.2	NP_001276737.1
CRYAB	NM_001289807.1 link	c.3G>A	p.Met1?	start_lost	Exon 2 of 4		NP_001276736.1
CRYAB	NM_001368245.1 link	c.3G>A	p.Met1?	start_lost	Exon 2 of 4		NP_001355174.1
CRYAB	NM_001885.3 link	c.3G>A	p.Met1?	start_lost	Exon 2 of 4		NP_001876.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYAB	ENST00000650687.2 link	c.3G>A	p.Met1?	start_lost	Exon 1 of 3		NM_001289808.2	ENSP00000499082.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000674

AC:

AN:

192938

AF XY:

0.0000484

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000884

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000147

AC:

AN:

1429202

Hom.:

Cov.:

AF XY:

0.0000127

AC XY:

AN XY:

707398

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33044

American (AMR)

AF:

0.00

AC:

AN:

38978

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25504

East Asian (EAS)

AF:

0.000545

AC:

AN:

38518

South Asian (SAS)

AF:

0.00

AC:

AN:

81758

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50982

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5670

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1095442

Other (OTH)

AF:

0.00

AC:

AN:

59306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41414

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000770

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00000462

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000498

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Mar 24, 2021

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 24, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31215171, 33834702) -

Dilated cardiomyopathy 1II

Pathogenic:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects the initiator methionine of the CRYAB mRNA. The next in-frame methionine is located at codon 68. This variant is present in population databases (rs397516686, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. Disruption of the initiator codon has been observed in individuals with autosomal recessive myofibrillar myopathy (PMID: 31215171, 33834702). ClinVar contains an entry for this variant (Variation ID: 44236). For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy

Pathogenic:1

Feb 13, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Met1? variant (CRYAB) has not been reported in the literature and has not be en previously detected by our laboratory. This variant is predicted to severely affect the synthesis of the CRYAB protein by disrupting the translation initiat ion start codon (ATG). In summary, this variant is likely to be pathogenic. -

not specified

Uncertain:1

May 04, 2022

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cataract 16 multiple types

Uncertain:1

Aug 10, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.43

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

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

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

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

M_CAP

Pathogenic

0.39

MetaRNN

Uncertain

0.53

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

MetaSVM

Uncertain

0.70

PhyloP100

7.7

PROVEAN

Benign

-2.2

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

REVEL

Pathogenic

0.82

Sift

Benign

0.096

T;.;T;T;T;T;T;T;T;D;D

Sift4G

Benign

0.17

T;T;T;T;T;T;.;.;T;.;.

Polyphen

1.0

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

Vest4

0.82

MutPred

0.74

Gain of catalytic residue at M1 (P = 0.0245);Gain of catalytic residue at M1 (P = 0.0245);Gain of catalytic residue at M1 (P = 0.0245);Gain of catalytic residue at M1 (P = 0.0245);Gain of catalytic residue at M1 (P = 0.0245);Gain of catalytic residue at M1 (P = 0.0245);Gain of catalytic residue at M1 (P = 0.0245);Gain of catalytic residue at M1 (P = 0.0245);Gain of catalytic residue at M1 (P = 0.0245);Gain of catalytic residue at M1 (P = 0.0245);Gain of catalytic residue at M1 (P = 0.0245);

MVP

0.96

ClinPred

0.68

GERP RS

5.1

PromoterAI

-0.12

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.59

gMVP

0.87

Mutation Taster

=26/174

disease causing (ClinVar)

(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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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