rs147328317

Positions:

• chr22-25207123-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_004076.5(CRYBB3):​c.547G>T​(p.Glu183Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000658 in 1,613,658 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (4 hom.)
• Consequence: CRYBB3 NM_004076.5 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 7.34

Genes affected

CRYBB3 (HGNC:2400): (crystallin beta B3) 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-B2. Mutations in this gene result in cataract congenital nuclear autosomal recessive type 2. [provided by RefSeq, Feb 2013]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00125 (191/152320) while in subpopulation AFR AF= 0.00257 (107/41576). AF 95% confidence interval is 0.00218. There are 3 homozygotes in gnomad4. There are 89 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYBB3	NM_004076.5	c.547G>T	p.Glu183Ter	stop_gained	6/6	ENST00000215855.7	NP_004067.1
CRYBB3	XM_047441147.1	c.547G>T	p.Glu183Ter	stop_gained	5/5		XP_047297103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYBB3	ENST00000215855.7	c.547G>T	p.Glu183Ter	stop_gained	6/6	1	NM_004076.5	ENSP00000215855	P1
CRYBB3	ENST00000404334.1	c.*62G>T		3_prime_UTR_variant	5/5	3		ENSP00000386123

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 191 AN: 152202 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00117 AC: 292 AN: 249886 Hom.: 2 AF XY: 0.00112 AC XY: 151 AN XY: 135420

Gnomad AFR exome AF: 0.00282

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.0190

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000311

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000596 AC: 871 AN: 1461338 Hom.: 4 Cov.: 31 AF XY: 0.000600 AC XY: 436 AN XY: 726998

Gnomad4 AFR exome AF: 0.00326

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.0183

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000143

Gnomad4 OTH exome AF: 0.00181

GnomAD4 genome AF: 0.00125 AC: 191 AN: 152320 Hom.: 3 Cov.: 32 AF XY: 0.00119 AC XY: 89 AN XY: 74486

Gnomad4 AFR AF: 0.00257

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00121 Hom.: 4

Bravo AF: 0.00165

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000923 AC: 112

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cataract 22 multiple types Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 15, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

CRYBB3-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 21, 2023

The CRYBB3 c.547G>T variant is predicted to result in premature protein termination (p.Glu183*). This variant occurs within the terminal exon of CRYBB3 and is predicted to shorten the coding sequence by 28 amino acids. This variant was reported in a family with congenital cataracts; however, all affected family members harbored a pathogenic variant in EPHA2. The CRYBB3 (p.Glu183*) did not segregate with the disorder and was excluded from further analysis (Reis et al. 2014. PubMed ID: 24940039). This variant was also reported in the heterozygous state in an individual with early-onset high myopia (eoHM); however, this patient also had additional variants in other candidate genes and all variants were reported to be maternally-inherited (Patient OFT-00332 in González-Iglesias et al 2022. PubMed ID: 35457050). This variant is reported in 1.9% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including two homozygous individuals (http://gnomad.broadinstitute.org/variant/22-25603090-G-T). Loss of function has not been a well documented cause of CRYBB3-related disease (Human Gene Mutation Database). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2023

CRYBB3: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D
Vest4		0.58
GERP RS		4.6

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: rs147328317; hg19: chr22-25603090;