rs777728814

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM5PP2PP3PP5

The NM_000394.4(CRYAA):c.161G>A(p.Arg54His) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in Lovd as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R54P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 9)

Exomes 𝑓: 0.000021 ( 3 hom. )

Failed GnomAD Quality Control

Consequence

CRYAA
NM_000394.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.25

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 was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a chain Alpha-crystallin A(1-168) (size 167) in uniprot entity CRYAA_HUMAN there are 44 pathogenic changes around while only 1 benign (98%) in NM_000394.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-43169259-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 68457.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). GenCC associations: The gene is linked to early-onset lamellar cataract, early-onset anterior polar cataract, total early-onset cataract, cataract - microcornea syndrome, early-onset nuclear cataract, cataract 9 multiple types.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.748

PP5

Variant 21-43169260-G-A is Pathogenic according to our data. Variant chr21-43169260-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYAA	NM_000394.4 link	c.161G>A	p.Arg54His	missense_variant	Exon 1 of 3	ENST00000291554.6	NP_000385.1	P02489
LOC107987300	XR_007067885.1 link	n.546+1777C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYAA	ENST00000291554.6 link	c.161G>A	p.Arg54His	missense_variant	Exon 1 of 3	1	NM_000394.4	ENSP00000291554.2		P02489
CRYAA	ENST00000482775.1 link	n.174G>A		non_coding_transcript_exon_variant	Exon 1 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

75758

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:

0.0000296

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

248326

AF XY:

0.0000223

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000207

AC:

AN:

724496

Hom.:

Cov.:

AF XY:

0.0000186

AC XY:

AN XY:

376148

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

16612

American (AMR)

AF:

0.00

AC:

AN:

35008

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17784

East Asian (EAS)

AF:

0.00

AC:

AN:

37128

South Asian (SAS)

AF:

0.0000141

AC:

AN:

70712

European-Finnish (FIN)

AF:

0.0000676

AC:

AN:

29566

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2816

European-Non Finnish (NFE)

AF:

0.0000250

AC:

AN:

479828

Other (OTH)

AF:

0.00

AC:

AN:

35042

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.017003), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.364

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:

0.0000132

AC:

AN:

75758

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

36438

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

18550

American (AMR)

AF:

0.00

AC:

AN:

8108

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1940

East Asian (EAS)

AF:

0.00

AC:

AN:

3948

South Asian (SAS)

AF:

0.00

AC:

AN:

2656

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5070

Middle Eastern (MID)

AF:

0.00

AC:

AN:

162

European-Non Finnish (NFE)

AF:

0.0000296

AC:

AN:

33824

Other (OTH)

AF:

0.00

AC:

AN:

880

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:

0.0000659

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.56

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.75

MetaSVM

Uncertain

0.63

MutationAssessor

Uncertain

2.6

PhyloP100

7.3

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.1

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0040

Sift4G

Benign

0.079

Polyphen

0.95

Vest4

0.48

MVP

0.91

MPC

1.3

ClinPred

0.87

GERP RS

4.9

PromoterAI

-0.056

Neutral

(source)

Varity_R

0.35

gMVP

0.69

Mutation Taster

=30/70

disease causing

(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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rs777728814

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over