rs781119593

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1PP2BP4_Moderate

The NM_000394.4(CRYAA):c.166G>A(p.Val56Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 9)

Exomes 𝑓: 0.000013 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

CRYAA
NM_000394.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.974

Publications

2 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: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
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: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.17500746).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000394.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYAA	NM_000394.4	MANE Select	c.166G>A	p.Val56Met	missense	Exon 1 of 3	NP_000385.1	P02489

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYAA	ENST00000291554.6	TSL:1 MANE Select	c.166G>A	p.Val56Met	missense	Exon 1 of 3	ENSP00000291554.2	P02489
	CRYAA	ENST00000482775.1	TSL:5	n.179G>A		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

75948

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000201

AC:

AN:

248248

AF XY:

0.0000223

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000535

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000127

AC:

AN:

707586

Hom.:

Cov.:

AF XY:

0.0000218

AC XY:

AN XY:

367470

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

16352

American (AMR)

AF:

0.0000288

AC:

AN:

34668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17706

East Asian (EAS)

AF:

0.00

AC:

AN:

36846

South Asian (SAS)

AF:

0.00

AC:

AN:

70088

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2714

European-Non Finnish (NFE)

AF:

0.0000172

AC:

AN:

465478

Other (OTH)

AF:

0.00

AC:

AN:

34354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.582

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000132

AC:

AN:

75948

Hom.:

Cov.:

AF XY:

0.0000274

AC XY:

AN XY:

36510

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

18764

American (AMR)

AF:

0.00

AC:

AN:

8122

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1926

East Asian (EAS)

AF:

0.00

AC:

AN:

3926

South Asian (SAS)

AF:

0.00

AC:

AN:

2638

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5048

Middle Eastern (MID)

AF:

0.00

AC:

AN:

170

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

33856

Other (OTH)

AF:

0.00

AC:

AN:

878

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cataract 9 multiple types (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.035

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.079

MetaRNN

Benign

0.18

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

1.1

PhyloP100

0.97

PrimateAI

Uncertain

0.61

PROVEAN

Benign

0.44

REVEL

Benign

0.21

Sift

Benign

0.22

Sift4G

Benign

0.22

Polyphen

0.046

Vest4

0.45

MutPred

0.33

Gain of loop (P = 0.1069)

MVP

0.67

MPC

0.46

ClinPred

0.15

GERP RS

4.9

PromoterAI

0.0094

Neutral

(source)

Varity_R

0.12

gMVP

0.41

Mutation Taster

=86/14

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over