11-111911560-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001289808.2(CRYAB):c.165G>A(p.Leu55=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,612,794 control chromosomes in the GnomAD database, including 349 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (23 hom., cov: 32)
  • Exomes 𝑓: 0.019 (326 hom.)
• Consequence: CRYAB NM_001289808.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.166

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 11-111911560-C-T is Benign according to our data. Variant chr11-111911560-C-T is described in ClinVar as [Benign]. Clinvar id is 44233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-111911560-C-T is described in Lovd as [Benign]. Variant chr11-111911560-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.166 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0132 (2014/152176) while in subpopulation SAS AF= 0.0239 (115/4812). AF 95% confidence interval is 0.0204. There are 23 homozygotes in gnomad4. There are 904 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 2015 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYAB	NM_001289808.2	c.165G>A	p.Leu55=	synonymous_variant	1/3	ENST00000650687.2
CRYAB	NM_001289807.1	c.165G>A	p.Leu55=	synonymous_variant	2/4
CRYAB	NM_001368245.1	c.165G>A	p.Leu55=	synonymous_variant	2/4
CRYAB	NM_001885.3	c.165G>A	p.Leu55=	synonymous_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYAB	ENST00000650687.2	c.165G>A	p.Leu55=	synonymous_variant	1/3		NM_001289808.2	P1

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2015 AN: 152058 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00377

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00885

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0237

Gnomad FIN AF: 0.0150

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0206

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.0154 AC: 3821 AN: 248196 Hom.: 55 AF XY: 0.0166 AC XY: 2222 AN XY: 134142

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.00458

Gnomad ASJ exome AF: 0.00691

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.0264

Gnomad FIN exome AF: 0.0164

Gnomad NFE exome AF: 0.0206

Gnomad OTH exome AF: 0.0151

GnomAD4 exome AF: 0.0191 AC: 27861 AN: 1460618 Hom.: 326 Cov.: 31 AF XY: 0.0191 AC XY: 13867 AN XY: 726454

Gnomad4 AFR exome AF: 0.00236

Gnomad4 AMR exome AF: 0.00525

Gnomad4 ASJ exome AF: 0.00591

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0263

Gnomad4 FIN exome AF: 0.0156

Gnomad4 NFE exome AF: 0.0210

Gnomad4 OTH exome AF: 0.0156

GnomAD4 genome AF: 0.0132 AC: 2014 AN: 152176 Hom.: 23 Cov.: 32 AF XY: 0.0121 AC XY: 904 AN XY: 74430

Gnomad4 AFR AF: 0.00376

Gnomad4 AMR AF: 0.00884

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0239

Gnomad4 FIN AF: 0.0150

Gnomad4 NFE AF: 0.0205

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0169 Hom.: 15

Bravo AF: 0.0119

Asia WGS AF: 0.00837 AC: 30 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2014	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 02, 2011	Leu55Leu in exon 1 of CRYAB: This variant is not expected to have clinical signi ficance because it does not alter an amino acid, is not located within the splic e consensus sequence, and has been identified in 1.5% (166/10758) of chromosomes from a broad, though clinically and ethnically unspecified population (dbSNP rs 2228387). Leu55Leu in exon 1 of CRYAB (rs2228387; allele frequency = 1.5%, 166/ 10758) -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 25, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 07, 2018	- -

Dilated cardiomyopathy 1II Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Myofibrillar Myopathy, Dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Fatal infantile hypertonic myofibrillar myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Cataract 16 multiple types Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	9.4
Dann	Benign	0.85

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: rs2228387; hg19: chr11-111782284;