22-25231717-G-A

Position:

• chr22-25231717-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000496.3(CRYBB2):​c.563G>A​(p.Arg188His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R188S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CRYBB2 NM_000496.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.57

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a domain Beta/gamma crystallin 'Greek key' 4 (size 42) in uniprot entity CRBB2_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_000496.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-25231716-C-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 22-25231717-G-A is Pathogenic according to our data. Variant chr22-25231717-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 280142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-25231717-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYBB2	NM_000496.3	c.563G>A	p.Arg188His	missense_variant	6/6	ENST00000398215.3	NP_000487.1
CRYBB2	XM_006724141.4	c.563G>A	p.Arg188His	missense_variant	6/6		XP_006724204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYBB2	ENST00000398215.3	c.563G>A	p.Arg188His	missense_variant	6/6	1	NM_000496.3	ENSP00000381273.2
CRYBB2	ENST00000651629.1	c.563G>A	p.Arg188His	missense_variant	6/6			ENSP00000498905.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 3 multiple types Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 188 of the CRYBB2 protein (p.Arg188His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with nonsyndromic congenital cataract (PMID: 22312185, 32498547). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 280142). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CRYBB2 function (PMID: 24120835, 24704203). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 25, 2019

Published functional studies demonstrate that the R188H variant perturbs the -crystallin oligomeric equilibrium, leading to increased aggregation and decreased stability of B2-crystallin ( Zhang et al., 2014).; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24704203, 22312185, 24120835, 32498547) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.3	M
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.90		Loss of MoRF binding (P = 0.0277);
MVP		0.97
MPC		1.5
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.89

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: rs886041410; hg19: chr22-25627684; COSMIC: COSV68005829;