rs17670506

chr22-25203882-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004076.5(CRYBB3):c.314G>A(p.Arg105Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0484 in 1,614,036 control chromosomes in the GnomAD database, including 2,226 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R105W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.045 (192 hom., cov: 32)
  • Exomes 𝑓: 0.049 (2034 hom.)
• Consequence: CRYBB3 NM_004076.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.57

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004779279).
• BP6: Variant 22-25203882-G-A is Benign according to our data. Variant chr22-25203882-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-25203882-G-A is described in Lovd as [Likely_benign]. Variant chr22-25203882-G-A is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYBB3	NM_004076.5	c.314G>A	p.Arg105Gln	missense_variant	4/6	ENST00000215855.7
CRYBB3	XM_047441147.1	c.314G>A	p.Arg105Gln	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYBB3	ENST00000215855.7	c.314G>A	p.Arg105Gln	missense_variant	4/6	1	NM_004076.5	P1
CRYBB3	ENST00000404334.1	c.314G>A	p.Arg105Gln	missense_variant	4/5	3

Frequencies

GnomAD3 genomes AF: 0.0447 AC: 6802 AN: 152112 Hom.: 192 Cov.: 32

Gnomad AFR AF: 0.0346

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.0387

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0251

Gnomad FIN AF: 0.0362

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0516

Gnomad OTH AF: 0.0556

GnomAD3 exomes AF: 0.0429 AC: 10794 AN: 251470 Hom.: 282 AF XY: 0.0433 AC XY: 5884 AN XY: 135910

Gnomad AFR exome AF: 0.0338

Gnomad AMR exome AF: 0.0317

Gnomad ASJ exome AF: 0.118

Gnomad EAS exome AF: 0.00103

Gnomad SAS exome AF: 0.0276

Gnomad FIN exome AF: 0.0397

Gnomad NFE exome AF: 0.0519

Gnomad OTH exome AF: 0.0533

GnomAD4 exome AF: 0.0488 AC: 71299 AN: 1461806 Hom.: 2034 Cov.: 32 AF XY: 0.0485 AC XY: 35253 AN XY: 727212

Gnomad4 AFR exome AF: 0.0346

Gnomad4 AMR exome AF: 0.0337

Gnomad4 ASJ exome AF: 0.123

Gnomad4 EAS exome AF: 0.000605

Gnomad4 SAS exome AF: 0.0275

Gnomad4 FIN exome AF: 0.0371

Gnomad4 NFE exome AF: 0.0515

Gnomad4 OTH exome AF: 0.0541

GnomAD4 genome AF: 0.0447 AC: 6798 AN: 152230 Hom.: 192 Cov.: 32 AF XY: 0.0442 AC XY: 3291 AN XY: 74438

Gnomad4 AFR AF: 0.0345

Gnomad4 AMR AF: 0.0387

Gnomad4 ASJ AF: 0.128

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0247

Gnomad4 FIN AF: 0.0362

Gnomad4 NFE AF: 0.0516

Gnomad4 OTH AF: 0.0550

Alfa AF: 0.0534 Hom.: 245

Bravo AF: 0.0453

TwinsUK AF: 0.0534 AC: 198

ALSPAC AF: 0.0522 AC: 201

ESP6500AA AF: 0.0315 AC: 139

ESP6500EA AF: 0.0541 AC: 465

ExAC AF: 0.0425 AC: 5163

Asia WGS AF: 0.0200 AC: 72 AN: 3478

EpiCase AF: 0.0550

EpiControl AF: 0.0568

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Congenital nuclear cataract Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 22, 2018

This variant is associated with the following publications: (PMID: 27307692) -

Cataract 22 multiple types Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.040
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.42	T;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D
MetaRNN	Benign	0.0048	T;T
MetaSVM	Uncertain	-0.027	T
MutationAssessor	Uncertain	2.9	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.68
MPC		0.66
ClinPred		0.018	T
GERP RS		3.5
Varity_R		0.73
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs17670506; hg19: chr22-25599849; COSMIC: COSV53195607;