22-26599663-AG-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001887.4(CRYBB1):c.585del(p.Tyr196IlefsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CRYBB1 NM_001887.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.546

Genes affected

CRYBB1 (HGNC:2397): (crystallin beta B1) Crystallins are separated into two classes: taxon-specific, or enzyme, and ubiquitous. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. Since lens central fiber cells lose their nuclei during development, these crystallins are made and then retained throughout life, making them extremely stable proteins. Mammalian lens crystallins are divided into alpha, beta, and gamma families; beta and gamma crystallins are also considered as a superfamily. Alpha and beta families are further divided into acidic and basic groups. Seven protein regions exist in crystallins: four homologous motifs, a connecting peptide, and N- and C-terminal extensions. Beta-crystallins, the most heterogeneous, differ by the presence of the C-terminal extension (present in the basic group, none in the acidic group). Beta-crystallins form aggregates of different sizes and are able to self-associate to form dimers or to form heterodimers with other beta-crystallins. This gene, a beta basic group member, undergoes extensive cleavage at its N-terminal extension during lens maturation. It is also a member of a gene cluster with beta-A4, beta-B2, and beta-B3. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-26599663-AG-A is Pathogenic according to our data. Variant chr22-26599663-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 574493.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYBB1	NM_001887.4	c.585del	p.Tyr196IlefsTer13	frameshift_variant	6/6	ENST00000647684.1
CRYBB1	XM_011529899.4	c.585del	p.Tyr196IlefsTer13	frameshift_variant	6/6
CRYBA4	XM_006724140.4	c.-239+2581del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYBB1	ENST00000647684.1	c.585del	p.Tyr196IlefsTer13	frameshift_variant	6/6		NM_001887.4	P1
	ENST00000668614.1	n.56+2581del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cataract 17 multiple types Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2018

For these reasons, this variant has been classified as Pathogenic. This variant has been observed to be de novo in an individual affected with congenital cataracts (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the CRYBB1 gene (p.Tyr196Ilefs*13). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 57 amino acids of the CRYBB1 protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1569203234; hg19: chr22-26995627;