rs2070894

chr11-111910113-G-Achr11-111910113-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.36

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]

ACMG classification

Verdict is Benign. Variant got -14 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_single_submitter, 1 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/exons	MANE	UniProt
CRYAB	NM_001289808.2	c.324+214C>T		intron_variant		ENST00000650687.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYAB	ENST00000650687.2	c.324+214C>T		intron_variant			NM_001289808.2	P1

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40713 AN: 151896 Hom.: 5659 Cov.: 32

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.: 6 AF XY: 0.277 AC XY: 83335 AN XY: 300556

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.: 32 AF XY: 0.268 AC XY: 19900 AN XY: 74308

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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

Other links and lift over

dbSNP: rs2070894; hg19: chr11-111780837;