11-111912374-G-C

Variant names:

• chr11-111912374-G-C
• rs2234702
• ENST00000526180.6:c.-224-426C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001885.3(CRYAB):​c.-198-452C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00573 in 182,470 control chromosomes in the GnomAD database, including 7 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 0.0055 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (2 hom.)
• Consequence: CRYAB NM_001885.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.382
• Publications: 4 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]

HSPB2 (HGNC:5247): (heat shock protein family B (small) member 2) The protein encoded by this gene belongs to the superfamily of small heat-shock proteins containing a conservative alpha-crystallin domain at the C-terminal part of the molecule. The protein is expressed preferentially in the heart and skeletal muscle. This protein regulates Myotonic Dystrophy Protein Kinase, which plays an important role in maintenance of muscle structure and function. [provided by RefSeq, Dec 2012]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001885.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYAB	NM_001289807.1		c.-198-452C>G		intron	N/A	NP_001276736.1	P02511
	CRYAB	NM_001368245.1		c.-198-452C>G		intron	N/A	NP_001355174.1	P02511
	CRYAB	NM_001885.3		c.-198-452C>G		intron	N/A	NP_001876.1	P02511

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYAB	ENST00000526180.6	TSL:1	c.-224-426C>G		intron	N/A	ENSP00000436051.1	P02511
	HSPB2	ENST00000941391.1		c.-456G>C		5_prime_UTR	Exon 1 of 2	ENSP00000611450.1
	CRYAB	ENST00000527899.6	TSL:2	c.-198-452C>G		intron	N/A	ENSP00000436089.2	P02511

Frequencies

GnomAD3 genomes AF: 0.00549 AC: 835 AN: 152088 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00527

GnomAD4 exome AF: 0.00694 AC: 210 AN: 30264 Hom.: 2 Cov.: 0 AF XY: 0.00651 AC XY: 100 AN XY: 15358

African (AFR) AF: 0.00110 AC: 1 AN: 910

American (AMR) AF: 0.00183 AC: 4 AN: 2186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 780

East Asian (EAS) AF: 0.00 AC: 0 AN: 1652

South Asian (SAS) AF: 0.00199 AC: 4 AN: 2008

European-Finnish (FIN) AF: 0.00200 AC: 3 AN: 1500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 104

European-Non Finnish (NFE) AF: 0.00991 AC: 192 AN: 19382

Other (OTH) AF: 0.00344 AC: 6 AN: 1742

GnomAD4 genome AF: 0.00549 AC: 835 AN: 152206 Hom.: 5 Cov.: 32 AF XY: 0.00480 AC XY: 357 AN XY: 74420

African (AFR) AF: 0.00226 AC: 94 AN: 41552

American (AMR) AF: 0.000916 AC: 14 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4816

European-Finnish (FIN) AF: 0.00189 AC: 20 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0101 AC: 689 AN: 67990

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.00123 Hom.: 0

Bravo AF: 0.00532

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.2
DANN	Benign	0.73
PhyloP100		-0.38
PromoterAI		-0.0067	Neutral
Mutation Taster		=100/0	polymorphism

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: rs2234702; hg19: chr11-111783098;