rs762550

Variant names:

• chr11-111912376-T-C
• rs762550
• ENST00000526180.6:c.-224-428A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• myofibrillar myopathy 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• cataract 16 multiple types

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• fatal infantile hypertonic myofibrillar myopathy

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet
• early-onset lamellar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset posterior polar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy 1II

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• 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 rank	MANE	Protein	UniProt
CRYAB	NM_001289807.1	c.-198-454A>G		intron_variant	Intron 1 of 3		NP_001276736.1
CRYAB	NM_001368245.1	c.-198-454A>G		intron_variant	Intron 1 of 3		NP_001355174.1
CRYAB	NM_001885.3	c.-198-454A>G		intron_variant	Intron 1 of 3		NP_001876.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYAB	ENST00000526180.6	c.-224-428A>G		intron_variant	Intron 1 of 3	1		ENSP00000436051.1
CRYAB	ENST00000527899.6	c.-198-454A>G		intron_variant	Intron 1 of 3	2		ENSP00000436089.2
CRYAB	ENST00000527950.5	c.-198-454A>G		intron_variant	Intron 1 of 3	5		ENSP00000437149.1

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

African (AFR) AF: 0.837 AC: 783 AN: 936

American (AMR) AF: 0.737 AC: 2138 AN: 2902

Ashkenazi Jewish (ASJ) AF: 0.641 AC: 504 AN: 786

East Asian (EAS) AF: 0.774 AC: 1282 AN: 1656

South Asian (SAS) AF: 0.693 AC: 1706 AN: 2462

European-Finnish (FIN) AF: 0.676 AC: 935 AN: 1384

Middle Eastern (MID) AF: 0.765 AC: 78 AN: 102

European-Non Finnish (NFE) AF: 0.645 AC: 12758 AN: 19770

Other (OTH) AF: 0.679 AC: 1246 AN: 1834

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

African (AFR) AF: 0.827 AC: 34307 AN: 41494

American (AMR) AF: 0.720 AC: 11016 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.639 AC: 2217 AN: 3472

East Asian (EAS) AF: 0.778 AC: 4008 AN: 5154

South Asian (SAS) AF: 0.643 AC: 3091 AN: 4808

European-Finnish (FIN) AF: 0.685 AC: 7240 AN: 10574

Middle Eastern (MID) AF: 0.764 AC: 223 AN: 292

European-Non Finnish (NFE) AF: 0.635 AC: 43165 AN: 67938

Other (OTH) AF: 0.694 AC: 1465 AN: 2112

Alfa AF: 0.698 Hom.: 6352

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
PhyloP100		-1.9
PromoterAI		0.020	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs762550; hg19: chr11-111783100;