dbSNP rs2070894: CRYAB:c.324+214C>T (chr11-111910113-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001289808.2(CRYAB):c.324+214C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 709,950 control chromosomes in the GnomAD database, including 27,418 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 5655 hom., cov: 32)

Exomes 𝑓: 0.28 ( 21763 hom. )

Consequence

CRYAB
NM_001289808.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.36

Variant links:

Genes affected

CRYAB (HGNC:2389): (crystallin alpha B) 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. 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. Elevated expression of alpha-B crystallin occurs in many neurological diseases; a missense mutation cosegregated in a family with a desmin-related myopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2019]

CRYAB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 11-111910113-G-A is Benign according to our data. Variant chr11-111910113-G-A is described in ClinVar as [Benign]. Clinvar id is 672477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYAB	NM_001289808.2 link	c.324+214C>T		intron_variant	Intron 2 of 2	ENST00000650687.2	NP_001276737.1	P02511V9HW27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYAB	ENST00000650687.2 link	c.324+214C>T		intron_variant	Intron 2 of 2		NM_001289808.2	ENSP00000499082.1		P02511

Frequencies

GnomAD3 genomes

AF:

0.268

AC:

40713

AN:

151896

Hom.:

5659

Cov.:

show subpopulations

Gnomad AFR

AF:

0.221

Gnomad AMI

AF:

0.173

Gnomad AMR

AF:

0.343

Gnomad ASJ

AF:

0.363

Gnomad EAS

AF:

0.180

Gnomad SAS

AF:

0.245

Gnomad FIN

AF:

0.256

Gnomad MID

AF:

0.313

Gnomad NFE

AF:

0.285

Gnomad OTH

AF:

0.305

GnomAD4 exome

AF:

0.277

AC:

154587

AN:

557938

Hom.:

21763

Cov.:

AF XY:

0.277

AC XY:

83335

AN XY:

300556

show subpopulations

Gnomad4 AFR exome

AF:

0.216

Gnomad4 AMR exome

AF:

0.303

Gnomad4 ASJ exome

AF:

0.357

Gnomad4 EAS exome

AF:

0.187

Gnomad4 SAS exome

AF:

0.258

Gnomad4 FIN exome

AF:

0.244

Gnomad4 NFE exome

AF:

0.286

Gnomad4 OTH exome

AF:

0.290

GnomAD4 genome

AF:

0.268

AC:

40711

AN:

152012

Hom.:

5655

Cov.:

AF XY:

0.268

AC XY:

19900

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.221

Gnomad4 AMR

AF:

0.342

Gnomad4 ASJ

AF:

0.363

Gnomad4 EAS

AF:

0.180

Gnomad4 SAS

AF:

0.244

Gnomad4 FIN

AF:

0.256

Gnomad4 NFE

AF:

0.285

Gnomad4 OTH

AF:

0.301

Alfa

AF:

0.224

Hom.:

987

Bravo

AF:

0.271

Asia WGS

AF:

0.227

AC:

791

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

5.5

DANN

Benign

0.67

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over