chr11-111908939-A-G

Position:

chr11-111908939-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PP3_StrongBS2

The NM_001289808.2(CRYAB):c.353T>C(p.Phe118Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,876 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 Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

CRYAB
NM_001289808.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 8.63

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 2 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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYAB	NM_001289808.2 linkuse as main transcript	c.353T>C	p.Phe118Ser	missense_variant	3/3	ENST00000650687.2	NP_001276737.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYAB	ENST00000650687.2 linkuse as main transcript	c.353T>C	p.Phe118Ser	missense_variant	3/3		NM_001289808.2	ENSP00000499082	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251120

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135764

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 20, 2015

The p.Phe118Ser variant in CRYAB has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction to ols and conservation analysis suggest that the p.Phe118Ser variant may impact th e protein, though this information is not predictive enough to determine pathoge nicity. In summary, the clinical significance of the p.Phe118Ser variant is unce rtain. -

Dilated cardiomyopathy 1II

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 07, 2023

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 118 of the CRYAB protein (p.Phe118Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CRYAB-related conditions. ClinVar contains an entry for this variant (Variation ID: 228540). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2024

The p.F118S variant (also known as c.353T>C), located in coding exon 3 of the CRYAB gene, results from a T to C substitution at nucleotide position 353. The phenylalanine at codon 118 is replaced by serine, an amino acid with highly dissimilar properties. This amino acid position is highly 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

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

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

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

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

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.97

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

H;.;.;H;H;H;H;H;.;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-7.1

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

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.99

MutPred

0.82

Gain of disorder (P = 0.002);.;.;Gain of disorder (P = 0.002);Gain of disorder (P = 0.002);Gain of disorder (P = 0.002);Gain of disorder (P = 0.002);Gain of disorder (P = 0.002);.;Gain of disorder (P = 0.002);.;Gain of disorder (P = 0.002);

MVP

1.0

MPC

1.2

ClinPred

1.0

GERP RS

5.7

Varity_R

0.99

gMVP

0.88

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