rs762550

Positions:

• chr11-111912376-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP5 BP4 BA1

The ENST00000526180.6(CRYAB):​c.-224-428A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.701 in 183,876 control chromosomes in the GnomAD database, including 45,773 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Likely pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.71 (38503 hom., cov: 31)
  • Exomes 𝑓: 0.67 (7270 hom.)
• Consequence: CRYAB ENST00000526180.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.91

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 -8 ACMG points.

• PP5: Variant 11-111912376-T-C is Pathogenic according to our data. Variant chr11-111912376-T-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84). . Strength limited to SUPPORTING due to the PP5.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.819 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYAB	NM_001289807.1	c.-198-454A>G		intron_variant
CRYAB	NM_001368245.1	c.-198-454A>G		intron_variant
CRYAB	NM_001885.3	c.-198-454A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYAB	ENST00000526180.6	c.-224-428A>G		intron_variant		1		P1
CRYAB	ENST00000527899.6	c.-198-454A>G		intron_variant		2		P1
CRYAB	ENST00000527950.5	c.-198-454A>G		intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.706 AC: 107305 AN: 151924 Hom.: 38469 Cov.: 31

Gnomad AFR AF: 0.827

Gnomad AMI AF: 0.724

Gnomad AMR AF: 0.721

Gnomad ASJ AF: 0.639

Gnomad EAS AF: 0.778

Gnomad SAS AF: 0.644

Gnomad FIN AF: 0.685

Gnomad MID AF: 0.768

Gnomad NFE AF: 0.635

Gnomad OTH AF: 0.696

GnomAD4 exome AF: 0.673 AC: 21430 AN: 31832 Hom.: 7270 Cov.: 0 AF XY: 0.672 AC XY: 10968 AN XY: 16328

Gnomad4 AFR exome AF: 0.837

Gnomad4 AMR exome AF: 0.737

Gnomad4 ASJ exome AF: 0.641

Gnomad4 EAS exome AF: 0.774

Gnomad4 SAS exome AF: 0.693

Gnomad4 FIN exome AF: 0.676

Gnomad4 NFE exome AF: 0.645

Gnomad4 OTH exome AF: 0.679

GnomAD4 genome AF: 0.706 AC: 107391 AN: 152044 Hom.: 38503 Cov.: 31 AF XY: 0.711 AC XY: 52860 AN XY: 74314

Gnomad4 AFR AF: 0.827

Gnomad4 AMR AF: 0.720

Gnomad4 ASJ AF: 0.639

Gnomad4 EAS AF: 0.778

Gnomad4 SAS AF: 0.643

Gnomad4 FIN AF: 0.685

Gnomad4 NFE AF: 0.635

Gnomad4 OTH AF: 0.694

Alfa AF: 0.694 Hom.: 6099

Bravo AF: 0.716

Asia WGS AF: 0.691 AC: 2403 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.55
DANN	Benign	0.76

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: rs762550; hg19: chr11-111783100;