21-43169244-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PP2PP3_StrongPP5_Moderate

The NM_000394.4(CRYAA):c.145C>T(p.Arg49Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R49H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 9)

Exomes 𝑓: 0.0000026 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CRYAA
NM_000394.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 1.68

Publications

57 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: Likely_pathogenic. The variant received 9 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

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, 0.951

PP5

Variant 21-43169244-C-T is Pathogenic according to our data. Variant chr21-43169244-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16959.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYAA	NM_000394.4 link	c.145C>T	p.Arg49Cys	missense_variant	Exon 1 of 3	ENST00000291554.6	NP_000385.1	P02489
LOC107987300	XR_007067885.1 link	n.546+1793G>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.145C>T	p.Arg49Cys	missense_variant	Exon 1 of 3	1	NM_000394.4	ENSP00000291554.2		P02489
CRYAA	ENST00000482775.1 link	n.158C>T		non_coding_transcript_exon_variant	Exon 1 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.0000260

AC:

AN:

76940

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000541

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000290

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000803

AC:

AN:

249112

AF XY:

0.00000741

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000259

AC:

AN:

772640

Hom.:

Cov.:

AF XY:

0.00000250

AC XY:

AN XY:

400204

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17392

American (AMR)

AF:

0.00

AC:

AN:

36882

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18458

East Asian (EAS)

AF:

0.00

AC:

AN:

38018

South Asian (SAS)

AF:

0.00

AC:

AN:

73038

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30646

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3140

European-Non Finnish (NFE)

AF:

0.00000386

AC:

AN:

518204

Other (OTH)

AF:

0.00

AC:

AN:

36862

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000260

AC:

AN:

76940

Hom.:

Cov.:

AF XY:

0.0000541

AC XY:

AN XY:

36992

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000541

AC:

AN:

18498

American (AMR)

AF:

0.00

AC:

AN:

8288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1998

East Asian (EAS)

AF:

0.00

AC:

AN:

4026

South Asian (SAS)

AF:

0.00

AC:

AN:

2754

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5188

Middle Eastern (MID)

AF:

0.00

AC:

AN:

174

European-Non Finnish (NFE)

AF:

0.0000290

AC:

AN:

34476

Other (OTH)

AF:

0.00

AC:

AN:

918

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.300

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000250

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cataract 9 multiple types

Pathogenic:2

Jun 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 49 of the CRYAA protein (p.Arg49Cys). This variant is present in population databases (rs74315441, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal dominant CRYAA-related conditions (PMID: 14512969). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16959). 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 CRYAA function (PMID: 14512969, 18056999, 22140512). For these reasons, this variant has been classified as Pathogenic. -

Oct 01, 2003

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Benign

0.74

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.52

MutationAssessor

Uncertain

2.4

PhyloP100

1.7

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.4

REVEL

Pathogenic

0.81

Sift

Uncertain

0.011

Sift4G

Benign

0.070

Polyphen

1.0

Vest4

0.95

MVP

0.97

MPC

1.2

ClinPred

0.94

GERP RS

4.0

PromoterAI

-0.032

Neutral

(source)

Varity_R

0.62

gMVP

0.81

Mutation Taster

=51/49

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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21-43169244-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over