Genetic Variant CRYAA:c.190-568C>T (chr21-43169949-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000394.4(CRYAA):c.190-568C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 10)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CRYAA
NM_000394.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.52

Publications

6 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_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYAA	NM_000394.4 link	c.190-568C>T		intron_variant	Intron 1 of 2	ENST00000291554.6	NP_000385.1
LOC107987300	XR_007067885.1 link	n.546+1088G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
CRYAA	ENST00000291554.6 link	c.190-568C>T	intron_variant	Intron 1 of 2	1	NM_000394.4	ENSP00000291554.2
CRYAA	ENST00000398133.5 link	c.129+96C>T	intron_variant	Intron 1 of 2	3		ENSP00000381201.1
CRYAA	ENST00000482775.1 link	n.270+349C>T	intron_variant	Intron 2 of 3	5
CRYAA	ENST00000398132.2 link	c.-383C>T	upstream_gene_variant		2		ENSP00000381200.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

80598

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000340

AC:

AN:

294194

Hom.:

AF XY:

0.00

AC XY:

AN XY:

157834

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:

5922

American (AMR)

AF:

0.00

AC:

AN:

16024

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8586

East Asian (EAS)

AF:

0.0000357

AC:

AN:

28046

South Asian (SAS)

AF:

0.00

AC:

AN:

41610

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25940

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1236

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

151306

Other (OTH)

AF:

0.00

AC:

AN:

15524

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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: AC0;AS_VQSR

AF:

0.00

AC:

AN:

80668

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

39378

African (AFR)

AF:

0.00

AC:

AN:

16686

American (AMR)

AF:

0.00

AC:

AN:

8476

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2118

East Asian (EAS)

AF:

0.00

AC:

AN:

4498

South Asian (SAS)

AF:

0.00

AC:

AN:

3456

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

160

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

37964

Other (OTH)

AF:

0.00

AC:

AN:

1042

Alfa

AF:

0.526

Hom.:

15555

Asia WGS

AF:

0.322

AC:

1124

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.091

(source)

DANN

Benign

0.42

PhyloP100

-1.5

PromoterAI

-0.0020

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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

Computational scores

Splicing

Publications

Other links and lift over