chr11-111911973-G-C

Variant names:

• chr11-111911973-G-C
• rs14133
• ENST00000526180.6:c.-224-25C>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The ENST00000526180.6(CRYAB):​c.-224-25C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 509,026 control chromosomes in the GnomAD database, including 19,715 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5628 hom., cov: 31)
  • Exomes 𝑓: 0.28 (14087 hom.)
• Consequence: CRYAB ENST00000526180.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.67
• Publications: 23 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 11-111911973-G-C is Benign according to our data. Variant chr11-111911973-G-C is described in ClinVar as Benign. ClinVar VariationId is 680264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYAB	NM_001289807.1	c.-198-51C>G		intron_variant	Intron 1 of 3		NP_001276736.1
CRYAB	NM_001368245.1	c.-198-51C>G		intron_variant	Intron 1 of 3		NP_001355174.1
CRYAB	NM_001885.3	c.-198-51C>G		intron_variant	Intron 1 of 3		NP_001876.1
CRYAB	NM_001289808.2	c.-249C>G		upstream_gene_variant		ENST00000650687.2	NP_001276737.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYAB	ENST00000650687.2	c.-249C>G		upstream_gene_variant			NM_001289808.2	ENSP00000499082.1

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40580 AN: 151920 Hom.: 5630 Cov.: 31

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.342

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.303

GnomAD4 exome AF: 0.278 AC: 99208 AN: 356988 Hom.: 14087 Cov.: 0 AF XY: 0.277 AC XY: 52020 AN XY: 187512

African (AFR) AF: 0.223 AC: 2369 AN: 10620

American (AMR) AF: 0.320 AC: 5035 AN: 15710

Ashkenazi Jewish (ASJ) AF: 0.360 AC: 4084 AN: 11332

East Asian (EAS) AF: 0.188 AC: 4492 AN: 23856

South Asian (SAS) AF: 0.255 AC: 9938 AN: 38948

European-Finnish (FIN) AF: 0.249 AC: 5152 AN: 20702

Middle Eastern (MID) AF: 0.332 AC: 521 AN: 1570

European-Non Finnish (NFE) AF: 0.288 AC: 61562 AN: 213482

Other (OTH) AF: 0.292 AC: 6055 AN: 20768

GnomAD4 genome AF: 0.267 AC: 40582 AN: 152038 Hom.: 5628 Cov.: 31 AF XY: 0.267 AC XY: 19830 AN XY: 74322

African (AFR) AF: 0.220 AC: 9132 AN: 41470

American (AMR) AF: 0.341 AC: 5206 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 1259 AN: 3468

East Asian (EAS) AF: 0.179 AC: 926 AN: 5164

South Asian (SAS) AF: 0.244 AC: 1175 AN: 4818

European-Finnish (FIN) AF: 0.256 AC: 2707 AN: 10578

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.284 AC: 19299 AN: 67958

Other (OTH) AF: 0.300 AC: 633 AN: 2112

Alfa AF: 0.267 Hom.: 710

Bravo AF: 0.270

Asia WGS AF: 0.227 AC: 792 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dilated cardiomyopathy 1II Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Benign	0.93
PhyloP100		2.7
PromoterAI		0.044	Neutral
Mutation Taster		=295/5	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: rs14133; hg19: chr11-111782697;