rs4252582

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001289808.2(CRYAB):c.60C>T(p.Pro20Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,608,418 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P20P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0011 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 102 hom. )

Consequence

CRYAB
NM_001289808.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.620

Publications

0 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 11-111911665-G-A is Benign according to our data. Variant chr11-111911665-G-A is described in ClinVar as Benign. ClinVar VariationId is 44239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.62 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00114 (174/152272) while in subpopulation SAS AF = 0.0349 (168/4818). AF 95% confidence interval is 0.0306. There are 6 homozygotes in GnomAd4. There are 115 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CRYAB	NM_001289808.2 link	c.60C>T	p.Pro20Pro	synonymous_variant	Exon 1 of 3	ENST00000650687.2	NP_001276737.1
CRYAB	NM_001289807.1 link	c.60C>T	p.Pro20Pro	synonymous_variant	Exon 2 of 4		NP_001276736.1
CRYAB	NM_001368245.1 link	c.60C>T	p.Pro20Pro	synonymous_variant	Exon 2 of 4		NP_001355174.1
CRYAB	NM_001885.3 link	c.60C>T	p.Pro20Pro	synonymous_variant	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.60C>T	p.Pro20Pro	synonymous_variant	Exon 1 of 3		NM_001289808.2	ENSP00000499082.1

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

173

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0346

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00481

AC:

1142

AN:

237432

AF XY:

0.00645

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000568

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000131

Gnomad OTH exome

AF:

0.00273

GnomAD4 exome

AF:

0.00240

AC:

3489

AN:

1456146

Hom.:

102

Cov.:

AF XY:

0.00350

AC XY:

2536

AN XY:

723594

show subpopulations

African (AFR)

AF:

0.000150

AC:

AN:

33438

American (AMR)

AF:

0.0000686

AC:

AN:

43712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25942

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39538

South Asian (SAS)

AF:

0.0382

AC:

3249

AN:

84972

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

52956

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000613

AC:

AN:

1109608

Other (OTH)

AF:

0.00254

AC:

153

AN:

60216

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

222

444

667

889

1111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.00114

AC:

174

AN:

152272

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

115

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41534

American (AMR)

AF:

0.0000654

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.0349

AC:

168

AN:

4818

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.000228

Hom.:

Bravo

AF:

0.000200

Asia WGS

AF:

0.0140

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Dec 16, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 23, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pro20Pro in exon 1 of CRYAB: This variant is not expected to have clinical signi ficance because it has been identified in 8.0% (14/176) of Gujarati Indian chrom osomes from a broad population by the HapMap Project (dbSNP rs4252582). -

Dilated cardiomyopathy 1II

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Myofibrillar myopathy 2

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Cardiomyopathy

Benign:1

May 10, 2016

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Fatal infantile hypertonic myofibrillar myopathy

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Jul 19, 2017

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

-0.62

PromoterAI

-0.024

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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