NM_000496.3:c.563G>A

Variant names:

• chr22-25231717-G-A
• rs886041410
• NM_000496.3:c.563G>A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 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. 12/21 in silico tools predict a damaging 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. R188L) has been classified as 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
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• cataract 3 multiple types

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• cataract - microcornea syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cerulean cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset posterior subcapsular cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset sutural cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pulverulent cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain 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 chr22-25231717-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 252952.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.0723 (below the threshold of 3.09). Trascript score misZ: 1.7369 (below the threshold of 3.09). GenCC associations: The gene is linked to cataract 3 multiple types, pulverulent cataract, cataract - microcornea syndrome, early-onset posterior subcapsular cataract, total early-onset cataract, early-onset nuclear cataract, cerulean cataract, early-onset sutural cataract.
• 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 VariationId is 280142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBB2	NM_000496.3	c.563G>A	p.Arg188His	missense_variant	Exon 6 of 6	ENST00000398215.3	NP_000487.1
CRYBB2	XM_006724141.4	c.563G>A	p.Arg188His	missense_variant	Exon 6 of 6		XP_006724204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYBB2	ENST00000398215.3	c.563G>A	p.Arg188His	missense_variant	Exon 6 of 6	1	NM_000496.3	ENSP00000381273.2
CRYBB2	ENST00000651629.1	c.563G>A	p.Arg188His	missense_variant	Exon 6 of 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

Oct 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 17, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24704203, 32498547, 24120835, 22312185) -

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
PhyloP100		9.6
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
Mutation Taster		=14/86	disease causing (ClinVar)

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

Other links and lift over

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