11-111912374-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP5 BP4 BS1_Supporting BS2

The ENST00000526180.6(CRYAB):c.-224-426C>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. Variant has been reported in Lovd as Likely pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.0055 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (2 hom.)
• Consequence: CRYAB ENST00000526180.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.382

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 Likely_benign. Variant got -5 ACMG points.

• PP5: Variant 11-111912374-G-C is Pathogenic according to our data. Variant chr11-111912374-G-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).. Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00549 (835/152206) while in subpopulation NFE AF= 0.0101 (689/67990). AF 95% confidence interval is 0.00951. There are 5 homozygotes in gnomad4. There are 357 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 835 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYAB	NM_001289807.1	c.-198-452C>G		intron_variant
CRYAB	NM_001368245.1	c.-198-452C>G		intron_variant
CRYAB	NM_001885.3	c.-198-452C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYAB	ENST00000526180.6	c.-224-426C>G		intron_variant		1		P1
CRYAB	ENST00000527899.6	c.-198-452C>G		intron_variant		2		P1
CRYAB	ENST00000527950.5	c.-198-452C>G		intron_variant		5		P1

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

Gnomad4 AFR exome AF: 0.00110

Gnomad4 AMR exome AF: 0.00183

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00199

Gnomad4 FIN exome AF: 0.00200

Gnomad4 NFE exome AF: 0.00991

Gnomad4 OTH exome AF: 0.00344

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

Gnomad4 AFR AF: 0.00226

Gnomad4 AMR AF: 0.000916

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00189

Gnomad4 NFE AF: 0.0101

Gnomad4 OTH AF: 0.00521

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	2.2
Dann	Benign	0.73

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: rs2234702; hg19: chr11-111783098;