NM_000394.4:c.61C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_000394.4(CRYAA):c.61C>T(p.Arg21Trp) 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. R21Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000024 ( 1 hom., 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:10

Conservation

PhyloP100: 5.45

Publications

27 publications found

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 Gene-Disease associations (from GenCC):

cataract 9 multiple types
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
cataract - microcornea syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset anterior polar cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset lamellar cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset nuclear cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
total early-onset cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CRYAA links:

LOC107987300 (HGNC:):

LOC107987300 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a chain Alpha-crystallin A(1-172) (size 171) in uniprot entity CRYAA_HUMAN there are 12 pathogenic changes around while only 1 benign (92%) in NM_000394.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-43169161-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 68461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.34778 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to early-onset lamellar cataract, cataract - microcornea syndrome, early-onset nuclear cataract, early-onset anterior polar cataract, total early-onset cataract, cataract 9 multiple types.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 21-43169160-C-T is Pathogenic according to our data. Variant chr21-43169160-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYAA	NM_000394.4 link	c.61C>T	p.Arg21Trp	missense_variant	Exon 1 of 3	ENST00000291554.6	NP_000385.1	P02489
LOC107987300	XR_007067885.1 link	n.546+1877G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYAA	ENST00000291554.6 link	c.61C>T	p.Arg21Trp	missense_variant	Exon 1 of 3	1	NM_000394.4	ENSP00000291554.2		P02489
CRYAA	ENST00000482775.1 link	n.74C>T		non_coding_transcript_exon_variant	Exon 1 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.0000241

AC:

AN:

82874

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000921

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

GnomAD2 exomes

AF:

0.00

AC:

AN:

251324

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

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

AF:

0.00

AC:

AN:

974658

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

490606

African (AFR)

AF:

0.00

AC:

AN:

18004

American (AMR)

AF:

0.00

AC:

AN:

36268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18490

East Asian (EAS)

AF:

0.00

AC:

AN:

38598

South Asian (SAS)

AF:

0.00

AC:

AN:

76746

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34480

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4038

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

706034

Other (OTH)

AF:

0.00

AC:

AN:

42000

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000241

AC:

AN:

82874

Hom.:

Cov.:

AF XY:

0.0000494

AC XY:

AN XY:

40486

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15962

American (AMR)

AF:

0.00

AC:

AN:

9032

Ashkenazi Jewish (ASJ)

AF:

0.000921

AC:

AN:

2172

East Asian (EAS)

AF:

0.00

AC:

AN:

4636

South Asian (SAS)

AF:

0.00

AC:

AN:

3540

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5988

Middle Eastern (MID)

AF:

0.00

AC:

AN:

188

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

39612

Other (OTH)

AF:

0.00

AC:

AN:

1074

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cataract 9 multiple types

Pathogenic:5

Genomics England Pilot Project, Genomics England

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 12, 2022

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS4, PM2, PP2, PP3, PP5 -

Jul 22, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine with tryptophan at codon 21 of the CRYAA protein (p.Arg21Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with autosomal dominant congenital cataracts (PMID: 23441109, 29386872). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68460). This variant has been reported to affect CRYAA protein function (PMID: 22045060, 22347476, 22140512). For these reasons, this variant has been classified as Pathogenic. -

Jun 07, 2019

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dr.Nikuei Genetic Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Mar 23, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect (Kore et al., 2012, Raju et al., 2011; Raju et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29914532, 17724170, 30078984, 26694549, 32883240, 34758253, 22140512, 22347476, 18587492, 29386872, 23441109, 22045060) -

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CRYAA-related disorder

Pathogenic:1

May 04, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CRYAA c.61C>T variant is predicted to result in the amino acid substitution p.Arg21Trp. This variant has been reported in several families with congenital cataracts (Hansen et al. 2007. PubMed ID: 17724170; Kondo et al. 2013. PubMed ID: 23441109; Ma et al. 2016. PubMed ID: 26694549). Functional studies have shown that this variant impacts the interaction with αB-Crystallin and causes increased protein aggregation (Raju et al. 2011. PubMed ID: 22140512; Raju et al. 2012. PubMed ID: 22347476). This variant has not been reported in a large population database, indicating this variant is rare. In addition, other variants impacting the same amino acid (p.Arg21Gln and p.Arg21Leu) have been documented in patients with congenital cataract (Laurie et al. 2013. PubMed ID: 23255486; Graw et al. 2006. PubMed ID: 16453125). Based on this evidence, the c.61C>T (p.Arg21Trp) variant is interpreted as pathogenic. -

Cataract 9, multiple types, with microcornea

Pathogenic:1

Sep 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Developmental cataract

Pathogenic:1

Jan 09, 2015

Eye Genetics Research Group, Children's Medical Research Institute

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.97

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.97

MutationAssessor

Uncertain

2.8

PhyloP100

5.4

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-6.0

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.88

MutPred

0.96

Gain of catalytic residue at Q25 (P = 0.1572);

MVP

0.95

MPC

1.2

ClinPred

1.0

GERP RS

4.9

PromoterAI

-0.017

Neutral

(source)

Varity_R

0.66

gMVP

0.90

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over