rs387907338

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3_ModeratePP5

The NM_001289808.2(CRYAB):c.166C>T(p.Arg56Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,612,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R56Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

CRYAB
NM_001289808.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 2.19

Publications

24 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 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.916

PP5

Variant 11-111911559-G-A is Pathogenic according to our data. Variant chr11-111911559-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41929.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYAB	NM_001289808.2 link	c.166C>T	p.Arg56Trp	missense_variant	Exon 1 of 3	ENST00000650687.2	NP_001276737.1	P02511V9HW27
CRYAB	NM_001289807.1 link	c.166C>T	p.Arg56Trp	missense_variant	Exon 2 of 4		NP_001276736.1	P02511V9HW27
CRYAB	NM_001368245.1 link	c.166C>T	p.Arg56Trp	missense_variant	Exon 2 of 4		NP_001355174.1
CRYAB	NM_001885.3 link	c.166C>T	p.Arg56Trp	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.166C>T	p.Arg56Trp	missense_variant	Exon 1 of 3		NM_001289808.2	ENSP00000499082.1		P02511

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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:

0.00000403

AC:

AN:

247880

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000547

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460452

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726374

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44504

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26058

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39674

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85788

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111574

Other (OTH)

AF:

0.0000166

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41432

American (AMR)

AF:

0.0000655

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000269

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1II

Pathogenic:1

Dec 20, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 56 of the CRYAB protein (p.Arg56Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal recessive juvenile cataracts and/or unexplained limb-girdle weakness (PMID: 19461931, 20141356, 32528171). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41929). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Myofibrillar myopathy 2

Pathogenic:1

Mar 14, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Cataract 16 multiple types

Pathogenic:1

May 15, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Cardiovascular phenotype

Uncertain:1

Feb 16, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R56W variant (also known as c.166C>T), located in coding exon 1 of the CRYAB gene, results from a C to T substitution at nucleotide position 166. The arginine at codon 56 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected in the homozygous state in individuals from families affected with juvenile cataracts; however, it has also been detected in the homozygous and heterozygous states in individuals without juvenile cataracts, and has been reported as a relatively common allele in both case and control cohorts (Safieh LA et al. Mol Vis, 2009 May;15:980-4; Khan AO et al. Ophthalmic Genet, 2010 Mar;31:30-6; Cui XJ et al. Medicine (Baltimore), 2017 Jun;96:e7158). This variant has been detected in a cohort of patients with features of skeletal myopathies; however, clinical detail was not provided (Töpf A et al. Genet Med, 2020 Sep;22:1478-1488). Functional studies suggest this variant may impact some aspects of protein function; however, the physiological relevance of these findings are unclear (Raju I et al. Biochem Biophys Res Commun. 2013 Jan;430(1):107-12; Muranova LK et al. Exp Eye Res. 2020 Aug;197:108091). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

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

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.94

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

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.92

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

MetaSVM

Uncertain

0.77

MutationAssessor

Uncertain

2.4

M;M;M;M;M;M;.;.;.;.;.

PhyloP100

2.2

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.9

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

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0020

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

Polyphen

1.0

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

Vest4

0.55

MutPred

0.76

Loss of disorder (P = 0.0063);Loss of disorder (P = 0.0063);Loss of disorder (P = 0.0063);Loss of disorder (P = 0.0063);Loss of disorder (P = 0.0063);Loss of disorder (P = 0.0063);Loss of disorder (P = 0.0063);Loss of disorder (P = 0.0063);Loss of disorder (P = 0.0063);Loss of disorder (P = 0.0063);Loss of disorder (P = 0.0063);

MVP

0.98

MPC

0.94

ClinPred

0.99

GERP RS

4.6

PromoterAI

-0.020

Neutral

(source)

Varity_R

0.87

gMVP

0.76

Mutation Taster

=3/97

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over