ENST00000526180.6:c.-224-150C>T

Variant names:

• chr11-111912098-G-A
• rs4252583
• ENST00000526180.6:c.-224-150C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 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 -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000526180.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYAB	NM_001289807.1		c.-198-176C>T		intron	N/A	NP_001276736.1
	CRYAB	NM_001368245.1		c.-198-176C>T		intron	N/A	NP_001355174.1
	CRYAB	NM_001885.3		c.-198-176C>T		intron	N/A	NP_001876.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYAB	ENST00000526180.6	TSL:1	c.-224-150C>T		intron	N/A	ENSP00000436051.1
	CRYAB	ENST00000527899.6	TSL:2	c.-198-176C>T		intron	N/A	ENSP00000436089.2
	CRYAB	ENST00000527950.5	TSL:5	c.-198-176C>T		intron	N/A	ENSP00000437149.1

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

African (AFR) AF: 0.0379 AC: 184 AN: 4856

American (AMR) AF: 0.00665 AC: 42 AN: 6316

Ashkenazi Jewish (ASJ) AF: 0.00208 AC: 7 AN: 3370

East Asian (EAS) AF: 0.000285 AC: 2 AN: 7016

South Asian (SAS) AF: 0.00 AC: 0 AN: 16362

European-Finnish (FIN) AF: 0.000219 AC: 1 AN: 4562

Middle Eastern (MID) AF: 0.0120 AC: 6 AN: 498

European-Non Finnish (NFE) AF: 0.000939 AC: 69 AN: 73492

Other (OTH) AF: 0.00427 AC: 28 AN: 6556

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

African (AFR) AF: 0.0396 AC: 1643 AN: 41510

American (AMR) AF: 0.00922 AC: 141 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68020

Other (OTH) AF: 0.00947 AC: 20 AN: 2112

Alfa AF: 0.0107 Hom.: 7

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

Jun 26, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.9
DANN	Benign	0.32
PhyloP100		1.0
PromoterAI		-0.31	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs4252583; hg19: chr11-111782822;