rs4252583

chr11-111912098-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000526180.6(CRYAB):c.-224-150C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00802 in 275,266 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (4 hom.)
• Consequence: CRYAB ENST00000526180.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.02

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=-0.81).
• BP6: Variant 11-111912098-G-A is Benign according to our data. Variant chr11-111912098-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1207966.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0123 (1869/152238) while in subpopulation AFR AF= 0.0396 (1643/41510). AF 95% confidence interval is 0.038. There are 34 homozygotes in gnomad4. There are 861 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1867 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYAB	NM_001289807.1	c.-198-176C>T		intron_variant
CRYAB	NM_001368245.1	c.-198-176C>T		intron_variant
CRYAB	NM_001885.3	c.-198-176C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYAB	ENST00000526180.6	c.-224-150C>T		intron_variant		1		P1
CRYAB	ENST00000527899.6	c.-198-176C>T		intron_variant		2		P1
CRYAB	ENST00000527950.5	c.-198-176C>T		intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1867 AN: 152120 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00923

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00957

GnomAD4 exome AF: 0.00276 AC: 339 AN: 123028 Hom.: 4 Cov.: 0 AF XY: 0.00231 AC XY: 149 AN XY: 64590

Gnomad4 AFR exome AF: 0.0379

Gnomad4 AMR exome AF: 0.00665

Gnomad4 ASJ exome AF: 0.00208

Gnomad4 EAS exome AF: 0.000285

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000219

Gnomad4 NFE exome AF: 0.000939

Gnomad4 OTH exome AF: 0.00427

GnomAD4 genome AF: 0.0123 AC: 1869 AN: 152238 Hom.: 34 Cov.: 32 AF XY: 0.0116 AC XY: 861 AN XY: 74434

Gnomad4 AFR AF: 0.0396

Gnomad4 AMR AF: 0.00922

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.00947

Alfa AF: 0.00924 Hom.: 6

Bravo AF: 0.0148

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	8.9
Dann	Benign	0.32

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4252583; hg19: chr11-111782822;