Genetic Variant CRYAA:p.Tyr18Tyr (chr21-43169153-C-T) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_000394.4(CRYAA):c.54C>T(p.Tyr18Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 980,440 control chromosomes in the GnomAD database, including 490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0076 ( 168 hom., cov: 11)

Exomes 𝑓: 0.0013 ( 490 hom. )

Failed GnomAD Quality Control

Consequence

CRYAA
NM_000394.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.11

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 21-43169153-C-T is Benign according to our data. Variant chr21-43169153-C-T is described in ClinVar as [Benign]. Clinvar id is 466610.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=1.11 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYAA	NM_000394.4 link	c.54C>T	p.Tyr18Tyr	synonymous_variant	Exon 1 of 3	ENST00000291554.6	NP_000385.1	P02489
LOC107987300	XR_007067885.1 link	n.546+1884G>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.54C>T	p.Tyr18Tyr	synonymous_variant	Exon 1 of 3	1	NM_000394.4	ENSP00000291554.2		P02489
CRYAA	ENST00000482775.1 link	n.67C>T		non_coding_transcript_exon_variant	Exon 1 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.00757

AC:

629

AN:

83104

Hom.:

169

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0369

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00417

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00532

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00921

GnomAD2 exomes

AF:

0.00129

AC:

324

AN:

251316

AF XY:

0.000876

show subpopulations

Gnomad AFR exome

AF:

0.0175

Gnomad AMR exome

AF:

0.000954

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.00126

AC:

1235

AN:

980440

Hom.:

490

Cov.:

AF XY:

0.00111

AC XY:

545

AN XY:

492986

show subpopulations

African (AFR)

AF:

0.0568

AC:

1000

AN:

17618

American (AMR)

AF:

0.00183

AC:

AN:

36048

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18368

East Asian (EAS)

AF:

0.00

AC:

AN:

38528

South Asian (SAS)

AF:

0.0000781

AC:

AN:

76780

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34532

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

4044

European-Non Finnish (NFE)

AF:

0.0000168

AC:

AN:

712530

Other (OTH)

AF:

0.00343

AC:

144

AN:

41992

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.578

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:

0.00759

AC:

631

AN:

83166

Hom.:

168

Cov.:

AF XY:

0.00754

AC XY:

307

AN XY:

40740

show subpopulations

African (AFR)

AF:

0.0369

AC:

582

AN:

15762

American (AMR)

AF:

0.00416

AC:

AN:

9126

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2198

East Asian (EAS)

AF:

0.00

AC:

AN:

4632

South Asian (SAS)

AF:

0.00

AC:

AN:

3586

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6020

Middle Eastern (MID)

AF:

0.00588

AC:

AN:

170

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

39890

Other (OTH)

AF:

0.00904

AC:

AN:

1106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.622

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00309

Hom.:

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cataract 9 multiple types

Benign:1

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: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

-0.49

CADD

Benign

7.8

(source)

DANN

Benign

0.60

PhyloP100

1.1

PromoterAI

-0.017

Neutral

(source)

Mutation Taster

=99/1

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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21-43169153-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