Genetic Variant CRYAA:c.189+14C>T (chr21-43169302-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_000394.4(CRYAA):c.189+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00049 ( 1 hom., cov: 9)

Exomes 𝑓: 0.00011 ( 8 hom. )

Failed GnomAD Quality Control

Consequence

CRYAA
NM_000394.4 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -5.00

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_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 21-43169302-C-T is Benign according to our data. Variant chr21-43169302-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1534897.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.189+14C>T		intron_variant	Intron 1 of 2	ENST00000291554.6	NP_000385.1	P02489
LOC107987300	XR_007067885.1 link	n.546+1735G>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.189+14C>T		intron_variant	Intron 1 of 2	1	NM_000394.4	ENSP00000291554.2		P02489
CRYAA	ENST00000482775.1 link	n.202+14C>T		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.000494

AC:

AN:

74928

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00146

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00125

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

GnomAD2 exomes

AF:

0.000208

AC:

AN:

245134

AF XY:

0.000195

show subpopulations

Gnomad AFR exome

AF:

0.00191

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000355

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000112

AC:

AN:

528248

Hom.:

Cov.:

AF XY:

0.000115

AC XY:

AN XY:

278744

show subpopulations

African (AFR)

AF:

0.00228

AC:

AN:

13144

American (AMR)

AF:

0.000440

AC:

AN:

29572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15148

East Asian (EAS)

AF:

0.00

AC:

AN:

33256

South Asian (SAS)

AF:

0.00

AC:

AN:

60852

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25924

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2082

European-Non Finnish (NFE)

AF:

0.0000125

AC:

AN:

320890

Other (OTH)

AF:

0.000438

AC:

AN:

27380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

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:

0.000493

AC:

AN:

75032

Hom.:

Cov.:

AF XY:

0.000388

AC XY:

AN XY:

36120

show subpopulations

African (AFR)

AF:

0.00146

AC:

AN:

18528

American (AMR)

AF:

0.00125

AC:

AN:

7994

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1932

East Asian (EAS)

AF:

0.00

AC:

AN:

3934

South Asian (SAS)

AF:

0.00

AC:

AN:

2590

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5018

Middle Eastern (MID)

AF:

0.00

AC:

AN:

140

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

33324

Other (OTH)

AF:

0.00

AC:

AN:

934

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000347

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cataract 9 multiple types

Benign:1

May 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.24

(source)

DANN

Benign

0.82

PhyloP100

-5.0

PromoterAI

0.038

Neutral

(source)

Mutation Taster

=100/0

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

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21-43169302-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over