rs74315489

Positions:

chr22-25231617-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000496.3(CRYBB2):c.463C>T(p.Gln155Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000616 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CRYBB2
NM_000496.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 4.68

Variant links:

Genes affected

CRYBB2 (HGNC:2398): (crystallin beta B2) 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, is part of a gene cluster with beta-A4, beta-B1, and beta-B3. A chain-terminating mutation was found to cause type 2 cerulean cataracts. [provided by RefSeq, Jul 2008]

CRYBB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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 22 pathogenic variants in the truncated region.

PP5

Variant 22-25231617-C-T is Pathogenic according to our data. Variant chr22-25231617-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-25231617-C-T is described in Lovd as [Pathogenic]. Variant chr22-25231617-C-T is described in Lovd as [Likely_pathogenic]. Variant chr22-25231617-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYBB2	NM_000496.3 linkuse as main transcript	c.463C>T	p.Gln155Ter	stop_gained	6/6	ENST00000398215.3
CRYBB2	XM_006724141.4 linkuse as main transcript	c.463C>T	p.Gln155Ter	stop_gained	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYBB2	ENST00000398215.3 linkuse as main transcript	c.463C>T	p.Gln155Ter	stop_gained	6/6	1	NM_000496.3	P1
CRYBB2	ENST00000651629.1 linkuse as main transcript	c.463C>T	p.Gln155Ter	stop_gained	6/6			P1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152174

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74466

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cataract 3 multiple types

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 09, 2023	This sequence change creates a premature translational stop signal (p.Gln155*) in the CRYBB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 51 amino acid(s) of the CRYBB2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with autosomal dominant congenital cataract (PMID: 9158139, 27385965, 29395391). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16949). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 15889016). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 11424921, 17234267). The variant has been reported to be associated with CRYBB2 related disorder (ClinVar ID: VCV000016949 / PMID: 9158139). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2007	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 29, 2022

Published functional studies demonstrate a damaging effect: reduced protein-protein interaction (Liu et al., 2005); Nonsense variant predicted to result in protein truncation, as the last 51 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11424921, 16179907, 28839118, 21245961, 9158139, 8812489, 17234267, 2240043, 10634616, 15889016, 24319337, 18449377, 28025620, 22846113, 19321936, 29395391, 27385965, 29652984, 30078984) -

CRYBB2-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 27, 2023

The CRYBB2 c.463C>T variant is predicted to result in premature protein termination (p.Gln155*). This variant segregated with autosomal dominant cerulean cataract in multiple families (Litt et al. 1997. PubMed ID: 9158139; Messina-Baas et al. 2016. PubMed ID: 27385965; Javadiyan et al. 2017. PubMed ID: 28839118; Ching et al. 2018. PubMed ID: 29395391; Zhang et al. 2018. PubMed ID: 30078984). In addition, there is evidence in the literature supporting that this variant likely arose from a gene conversion event between the CRYBB2 gene and its pseudogene, CRYBB2P1 (Vanita et al. 2001. PubMed ID: 11424921; Bateman et al. 2007. PubMed ID: 17234267). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in CRYBB2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Developmental cataract

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Ophthalmology, Flinders University

Jul 29, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.97

MutationTaster

Benign

1.0

Vest4

0.79

GERP RS

4.2

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over