Variant 11-111908783-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_001289808.2(CRYAB):c.509C>A(p.Thr170Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T170I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CRYAB
NM_001289808.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.60

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a glycosylation_site O-linked (GlcNAc) threonine (size 0) in uniprot entity CRYAB_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23306176).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYAB	NM_001289808.2 linkuse as main transcript	c.509C>A	p.Thr170Asn	missense_variant	3/3	ENST00000650687.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYAB	ENST00000650687.2 linkuse as main transcript	c.509C>A	p.Thr170Asn	missense_variant	3/3		NM_001289808.2	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460606

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726632

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

May 04, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.044

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.18

T;T;T;T;T;T;T;T;T;T;.

Eigen

Benign

-0.18

Eigen_PC

Benign

0.063

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

.;.;.;T;.;.;.;.;T;.;T

M_CAP

Benign

0.039

MetaRNN

Benign

0.23

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.0052

MutationAssessor

Benign

0.55

N;.;.;N;N;N;N;N;.;.;.

MutationTaster

Benign

0.99

N;N;N;N;N;N;N

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.31

N;N;N;.;N;N;N;N;N;N;N

REVEL

Benign

0.21

Sift

Benign

0.082

T;T;T;.;T;T;T;T;T;T;T

Sift4G

Benign

0.52

T;T;T;T;T;T;T;T;.;.;.

Polyphen

0.028

B;.;.;B;B;B;B;B;.;.;.

Vest4

0.12

MutPred

0.19

Loss of glycosylation at T170 (P = 0.0024);.;.;Loss of glycosylation at T170 (P = 0.0024);Loss of glycosylation at T170 (P = 0.0024);Loss of glycosylation at T170 (P = 0.0024);Loss of glycosylation at T170 (P = 0.0024);Loss of glycosylation at T170 (P = 0.0024);.;Loss of glycosylation at T170 (P = 0.0024);.;

MVP

0.97

MPC

0.33

ClinPred

0.38

GERP RS

5.1

Varity_R

0.16

gMVP

0.22

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over