rs14133

Positions:

• chr11-111911973-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The ENST00000526180.6(CRYAB):​c.-224-25C>G 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 509,026 control chromosomes in the GnomAD database, including 19,715 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5628 hom., cov: 31)
  • Exomes 𝑓: 0.28 (14087 hom.)
• Consequence: CRYAB ENST00000526180.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.67

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 11-111911973-G-C is Benign according to our data. Variant chr11-111911973-G-C is described in ClinVar as [Benign]. Clinvar id is 680264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYAB	NM_001289807.1	c.-198-51C>G		intron_variant
CRYAB	NM_001368245.1	c.-198-51C>G		intron_variant
CRYAB	NM_001885.3	c.-198-51C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYAB	ENST00000526180.6	c.-224-25C>G		intron_variant		1		P1
CRYAB	ENST00000227251.7	c.-148C>G		5_prime_UTR_variant	1/4	5		P1
CRYAB	ENST00000651164.1	c.-159C>G		5_prime_UTR_variant	1/4			P1

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40580 AN: 151920 Hom.: 5630 Cov.: 31

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.342

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.303

GnomAD4 exome AF: 0.278 AC: 99208 AN: 356988 Hom.: 14087 Cov.: 0 AF XY: 0.277 AC XY: 52020 AN XY: 187512

Gnomad4 AFR exome AF: 0.223

Gnomad4 AMR exome AF: 0.320

Gnomad4 ASJ exome AF: 0.360

Gnomad4 EAS exome AF: 0.188

Gnomad4 SAS exome AF: 0.255

Gnomad4 FIN exome AF: 0.249

Gnomad4 NFE exome AF: 0.288

Gnomad4 OTH exome AF: 0.292

GnomAD4 genome AF: 0.267 AC: 40582 AN: 152038 Hom.: 5628 Cov.: 31 AF XY: 0.267 AC XY: 19830 AN XY: 74322

Gnomad4 AFR AF: 0.220

Gnomad4 AMR AF: 0.341

Gnomad4 ASJ AF: 0.363

Gnomad4 EAS AF: 0.179

Gnomad4 SAS AF: 0.244

Gnomad4 FIN AF: 0.256

Gnomad4 NFE AF: 0.284

Gnomad4 OTH AF: 0.300

Alfa AF: 0.267 Hom.: 710

Bravo AF: 0.270

Asia WGS AF: 0.227 AC: 792 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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. -

Dilated cardiomyopathy 1II Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Benign	0.93

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: rs14133; hg19: chr11-111782697;