22-25205229-C-G

Position:

• chr22-25205229-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_004076.5(CRYBB3):​c.337C>G​(p.His113Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.632 in 1,613,446 control chromosomes in the GnomAD database, including 326,771 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (27457 hom., cov: 31)
  • Exomes 𝑓: 0.64 (299314 hom.)
• Consequence: CRYBB3 NM_004076.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 7.24

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 -18 ACMG points.

• PM1: In a chain Beta-crystallin B3 (size 210) in uniprot entity CRBB3_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_004076.5
• BP4: Computational evidence support a benign effect (MetaRNN=1.3479986E-6).
• BP6: Variant 22-25205229-C-G is Benign according to our data. Variant chr22-25205229-C-G is described in ClinVar as [Benign]. Clinvar id is 259229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-25205229-C-G is described in Lovd as [Benign]. Variant chr22-25205229-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.911 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYBB3	NM_004076.5	c.337C>G	p.His113Asp	missense_variant	5/6	ENST00000215855.7	NP_004067.1
CRYBB3	XM_047441147.1	c.337C>G	p.His113Asp	missense_variant	4/5		XP_047297103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYBB3	ENST00000215855.7	c.337C>G	p.His113Asp	missense_variant	5/6	1	NM_004076.5	ENSP00000215855	P1
CRYBB3	ENST00000404334.1	c.327+1334C>G		intron_variant		3		ENSP00000386123

Frequencies

GnomAD3 genomes AF: 0.593 AC: 89958 AN: 151826 Hom.: 27441 Cov.: 31

Gnomad AFR AF: 0.457

Gnomad AMI AF: 0.703

Gnomad AMR AF: 0.674

Gnomad ASJ AF: 0.677

Gnomad EAS AF: 0.934

Gnomad SAS AF: 0.700

Gnomad FIN AF: 0.574

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.626

GnomAD3 exomes AF: 0.663 AC: 166523 AN: 251290 Hom.: 56765 AF XY: 0.662 AC XY: 89848 AN XY: 135810

Gnomad AFR exome AF: 0.451

Gnomad AMR exome AF: 0.775

Gnomad ASJ exome AF: 0.681

Gnomad EAS exome AF: 0.930

Gnomad SAS exome AF: 0.687

Gnomad FIN exome AF: 0.584

Gnomad NFE exome AF: 0.622

Gnomad OTH exome AF: 0.666

GnomAD4 exome AF: 0.637 AC: 930251 AN: 1461502 Hom.: 299314 Cov.: 66 AF XY: 0.638 AC XY: 463490 AN XY: 727024

Gnomad4 AFR exome AF: 0.443

Gnomad4 AMR exome AF: 0.763

Gnomad4 ASJ exome AF: 0.684

Gnomad4 EAS exome AF: 0.921

Gnomad4 SAS exome AF: 0.681

Gnomad4 FIN exome AF: 0.587

Gnomad4 NFE exome AF: 0.624

Gnomad4 OTH exome AF: 0.646

GnomAD4 genome AF: 0.592 AC: 90005 AN: 151944 Hom.: 27457 Cov.: 31 AF XY: 0.597 AC XY: 44324 AN XY: 74246

Gnomad4 AFR AF: 0.456

Gnomad4 AMR AF: 0.675

Gnomad4 ASJ AF: 0.677

Gnomad4 EAS AF: 0.933

Gnomad4 SAS AF: 0.698

Gnomad4 FIN AF: 0.574

Gnomad4 NFE AF: 0.619

Gnomad4 OTH AF: 0.630

Alfa AF: 0.626 Hom.: 21216

Bravo AF: 0.599

TwinsUK AF: 0.627 AC: 2324

ALSPAC AF: 0.619 AC: 2387

ESP6500AA AF: 0.467 AC: 2059

ESP6500EA AF: 0.631 AC: 5425

ExAC AF: 0.656 AC: 79603

Asia WGS AF: 0.806 AC: 2806 AN: 3478

EpiCase AF: 0.625

EpiControl AF: 0.627

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cataract 22 multiple types Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -

Congenital nuclear cataract Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.75
DEOGEN2	Benign	0.0055	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.022	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.8	N
MutationTaster	Benign	0.99	P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	4.4	N
REVEL	Benign	0.21
Sift	Benign	0.83	T
Sift4G	Benign	0.64	T
Polyphen		0.0	B
Vest4		0.059
MPC		0.21
ClinPred		0.0085	T
GERP RS		5.3
Varity_R		0.14
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs9608378; hg19: chr22-25601196; COSMIC: COSV53194229;