rs1114167341

Positions:

• chr11-111908966-T-C
• chr11-111908966-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_001289808.2(CRYAB):​c.326A>G​(p.Asp109Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D109H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRYAB NM_001289808.2 missense, splice_region
• Scores: Splicing: ADA: 0.8727
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.41

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a domain sHSP (size 108) in uniprot entity CRYAB_HUMAN there are 10 pathogenic changes around while only 4 benign (71%) in NM_001289808.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-111908967-C-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 11-111908966-T-C is Pathogenic according to our data. Variant chr11-111908966-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265829.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-111908966-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYAB	NM_001289808.2	c.326A>G	p.Asp109Gly	missense_variant, splice_region_variant	3/3	ENST00000650687.2	NP_001276737.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYAB	ENST00000650687.2	c.326A>G	p.Asp109Gly	missense_variant, splice_region_variant	3/3		NM_001289808.2	ENSP00000499082	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated cardiomyopathy 1II Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 109 of the CRYAB protein (p.Asp109Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant restrictive cardiomyopathy (PMID: 28493373). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 265829). 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. Experimental studies have shown that this missense change affects CRYAB function (PMID: 28493373). This variant disrupts the p.Asp109 amino acid residue in CRYAB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21920752, 23194663, 26627873). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Cardiomyopathy, familial restrictive, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen

May 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;T;T;D;D;D;D;D;T;D;.;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;.;.;D;.;.;.;.;D;.;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.3	M;.;.;M;M;M;M;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-6.0	D;D;D;.;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D;.;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;.;.;.;.
Polyphen		1.0	D;.;.;D;D;D;D;D;.;.;.;.
Vest4		0.84
MutPred		0.78		Loss of solvent accessibility (P = 0.1279);.;.;Loss of solvent accessibility (P = 0.1279);Loss of solvent accessibility (P = 0.1279);Loss of solvent accessibility (P = 0.1279);Loss of solvent accessibility (P = 0.1279);Loss of solvent accessibility (P = 0.1279);.;Loss of solvent accessibility (P = 0.1279);.;Loss of solvent accessibility (P = 0.1279);
MVP		0.99
MPC		1.1
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.87
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs1114167341; hg19: chr11-111779690;