Genetic Variant CRYAA:p.Phe27Phe (chr21-43169180-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_ModerateBP6_ModerateBP7

The NM_000394.4(CRYAA):c.81C>T(p.Phe27Phe) variant causes a synonymous 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 0.000025 ( 0 hom., cov: 10)

Exomes 𝑓: 0.000043 ( 7 hom. )

Failed GnomAD Quality Control

Consequence

CRYAA
NM_000394.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.600

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.3).

BP6

Variant 21-43169180-C-T is Benign according to our data. Variant chr21-43169180-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 697528.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.6 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYAA	NM_000394.4 link	c.81C>T	p.Phe27Phe	synonymous_variant	Exon 1 of 3	ENST00000291554.6	NP_000385.1	P02489
LOC107987300	XR_007067885.1 link	n.546+1857G>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.81C>T	p.Phe27Phe	synonymous_variant	Exon 1 of 3	1	NM_000394.4	ENSP00000291554.2		P02489
CRYAA	ENST00000482775.1 link	n.94C>T		non_coding_transcript_exon_variant	Exon 1 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.0000245

AC:

AN:

81478

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:

0.0000518

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000996

AC:

AN:

251044

AF XY:

0.0000810

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000428

AC:

AN:

887300

Hom.:

Cov.:

AF XY:

0.0000398

AC XY:

AN XY:

451768

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17932

American (AMR)

AF:

0.00

AC:

AN:

36590

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18428

East Asian (EAS)

AF:

0.000130

AC:

AN:

38518

South Asian (SAS)

AF:

0.00

AC:

AN:

75092

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33052

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3836

European-Non Finnish (NFE)

AF:

0.0000513

AC:

AN:

624054

Other (OTH)

AF:

0.0000251

AC:

AN:

39798

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

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:

0.0000245

AC:

AN:

81478

Hom.:

Cov.:

AF XY:

0.0000253

AC XY:

AN XY:

39596

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

16362

American (AMR)

AF:

0.00

AC:

AN:

8848

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:

3408

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5766

Middle Eastern (MID)

AF:

0.00

AC:

AN:

182

European-Non Finnish (NFE)

AF:

0.0000518

AC:

AN:

38590

Other (OTH)

AF:

0.00

AC:

AN:

1062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000103

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 10, 2018

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

-0.30

CADD

Benign

(source)

DANN

Benign

0.80

PhyloP100

-0.60

PromoterAI

-0.038

Neutral

(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.

21-43169180-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