rs2330991

Variant names:

• chr22-25229562-C-T
• rs2330991
• NM_000496.3:c.433C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP2

The NM_000496.3(CRYBB2):​c.433C>T​(p.Arg145Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R145P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CRYBB2 NM_000496.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.137
• Publications: 12 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000496.3
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBB2	NM_000496.3	c.433C>T	p.Arg145Trp	missense_variant	Exon 5 of 6	ENST00000398215.3	NP_000487.1
CRYBB2	XM_006724141.4	c.433C>T	p.Arg145Trp	missense_variant	Exon 5 of 6		XP_006724204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYBB2	ENST00000398215.3	c.433C>T	p.Arg145Trp	missense_variant	Exon 5 of 6	1	NM_000496.3	ENSP00000381273.2
CRYBB2	ENST00000651629.1	c.433C>T	p.Arg145Trp	missense_variant	Exon 5 of 6			ENSP00000498905.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152260 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251396 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727228

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1112000

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000129320), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74388

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000723 AC: 3 AN: 41474

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00251027), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000501 Hom.: 0

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

CRYBB2-related disorder Uncertain:1

Sep 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CRYBB2 c.433C>T variant is predicted to result in the amino acid substitution p.Arg145Trp. This variant along with two other missense variants in CRYBB2 (p.Gln147Arg and p.Thr150Met) have been reported in the heterozygous state in patients and families with congenital cataracts (Family CC00133 in Hansen et al. 2009. PubMed ID: 19182255; Garnai et al. 2014. PubMed ID: 25489230; Zhuang et al. 2019. PubMed ID: 31523120). Using primers specific to both CRYBB2 and its pseudogene (CRYBB2P1), Garnai et al. were able to show that the three variants resulted from a de novo gene conversion event involving the transfer of ~270 base pairs from the pseudogene to CRYBB2 (Garnai et al. 2014. PubMed ID: 25489230). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD. Of note, another large family with congenital cataracts was reported to have the CRYBB2 p.Gln147Arg and p.Thr150Met variants without the p.Arg145Trp variant. This family also had additional variants in other cataract related genes (GJA3 and HSF4) (Lv et al. 2014. PubMed ID: 24637349). To our knowledge, studies analyzing the functional consequences of these variants either individually or in combination with one another have not been completed. At PreventionGenetics, we have detected the c.433C>T (p.Arg145Trp) and the c.440A>G (p.Gln147Arg) variants together in another patient undergoing testing for early-onset cataracts (Internal Data). Although we suspect that the c.433C>T (p.Arg145Trp) variant may be pathogenic, at this time, its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		0.14
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.56		Loss of disorder (P = 0.0262);
MVP		0.75
MPC		1.3
ClinPred		0.98	D
GERP RS		1.2
Varity_R		0.70
Mutation Taster		=17/83	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs2330991; hg19: chr22-25625529;