rs387907338

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PP3_ModeratePP5BS2

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. R56P) 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a domain sHSP (size 108) in uniprot entity CRYAB_HUMAN there are 16 pathogenic changes around while only 6 benign (73%) in NM_001289808.2

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 id is 41929.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}. Variant chr11-111911559-G-A is described in Lovd as [Likely_pathogenic].

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CRYAB	NM_001289808.2 linkuse as main transcript	c.166C>T	p.Arg56Trp	missense_variant	1/3	ENST00000650687.2
CRYAB	NM_001289807.1 linkuse as main transcript	c.166C>T	p.Arg56Trp	missense_variant	2/4
CRYAB	NM_001368245.1 linkuse as main transcript	c.166C>T	p.Arg56Trp	missense_variant	2/4
CRYAB	NM_001885.3 linkuse as main transcript	c.166C>T	p.Arg56Trp	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYAB	ENST00000650687.2 linkuse as main transcript	c.166C>T	p.Arg56Trp	missense_variant	1/3		NM_001289808.2	P1

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

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460452

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726374

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000279

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 20, 2023

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

Likely pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 14, 2024

- -

Cataract 16 multiple types

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 15, 2009

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2024

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

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;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

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

Varity_R

0.87

gMVP

0.76

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over