rs397515624

Positions:

chr21-43169133-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000394.4(CRYAA):c.34C>T(p.Arg12Cys) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. 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. R12H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 11)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CRYAA
NM_000394.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 5.49

Variant links:

Genes affected

CRYAA (HGNC:2388): (crystallin alpha A) 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. Post-translational modifications decrease the ability to chaperone. 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. Defects in this gene cause autosomal dominant congenital cataract (ADCC). [provided by RefSeq, Jan 2014]

CRYAA links:

LOC107987300 (HGNC:):

LOC107987300 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a chain Alpha-crystallin A(1-168) (size 167) in uniprot entity CRYAA_HUMAN there are 43 pathogenic changes around while only 1 benign (98%) in NM_000394.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 21-43169133-C-T is Pathogenic according to our data. Variant chr21-43169133-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43169133-C-T is described in Lovd as [Pathogenic]. Variant chr21-43169133-C-T is described in Lovd as [Pathogenic]. Variant chr21-43169133-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYAA	NM_000394.4 linkuse as main transcript	c.34C>T	p.Arg12Cys	missense_variant	1/3	ENST00000291554.6
LOC107987300	XR_007067885.1 linkuse as main transcript	n.546+1904G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYAA	ENST00000291554.6 linkuse as main transcript	c.34C>T	p.Arg12Cys	missense_variant	1/3	1	NM_000394.4	P1
CRYAA	ENST00000482775.1 linkuse as main transcript	n.47C>T		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251338

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135852

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

961744

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

482826

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000936

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cataract 9 multiple types

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 25, 2020	For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect CRYAA protein function (PMID: 22140512, 22347476). This variant has been observed in individuals with autosomal dominant congenital cataracts (PMID: 17724170, 19503744, 22045060, 23508780) and segregates with disease in families (PMID: 19503744, 23508780). ClinVar contains an entry for this variant (Variation ID: 68459). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 12 of the CRYAA protein (p.Arg12Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jul 28, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Sep 29, 2021	- -

not provided

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Abnormality of the eye

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Cataract 9, multiple types, with microcornea

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2013

- -

Developmental cataract

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Dept. Genetics and Cancer, Menzies Institute for Medical Research, University of Tasmania

May 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.97

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.84

MutPred

0.90

Gain of catalytic residue at R12 (P = 0.011);

MVP

0.99

MPC

1.4

ClinPred

0.99

GERP RS

4.9

Varity_R

0.85

gMVP

0.86

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