rs8140949

Positions:

• chr22-25231637-G-A

Variant summary

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

The NM_000496.3(CRYBB2):​c.483G>A​(p.Gly161=) variant causes a synonymous change. The variant allele was found at a frequency of 0.236 in 1,613,704 control chromosomes in the GnomAD database, including 48,773 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5024 hom., cov: 31)
  • Exomes 𝑓: 0.23 (43749 hom.)
• Consequence: CRYBB2 NM_000496.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.61

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 22-25231637-G-A is Benign according to our data. Variant chr22-25231637-G-A is described in ClinVar as [Benign]. Clinvar id is 256283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-25231637-G-A is described in Lovd as [Benign]. Variant chr22-25231637-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYBB2	NM_000496.3	c.483G>A	p.Gly161=	synonymous_variant	6/6	ENST00000398215.3
CRYBB2	XM_006724141.4	c.483G>A	p.Gly161=	synonymous_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYBB2	ENST00000398215.3	c.483G>A	p.Gly161=	synonymous_variant	6/6	1	NM_000496.3	P1
CRYBB2	ENST00000651629.1	c.483G>A	p.Gly161=	synonymous_variant	6/6			P1

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37829 AN: 151894 Hom.: 5019 Cov.: 31

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.421

Gnomad SAS AF: 0.449

Gnomad FIN AF: 0.180

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.261

GnomAD3 exomes AF: 0.277 AC: 69048 AN: 249516 Hom.: 10658 AF XY: 0.280 AC XY: 37852 AN XY: 135018

Gnomad AFR exome AF: 0.279

Gnomad AMR exome AF: 0.313

Gnomad ASJ exome AF: 0.271

Gnomad EAS exome AF: 0.428

Gnomad SAS exome AF: 0.430

Gnomad FIN exome AF: 0.188

Gnomad NFE exome AF: 0.217

Gnomad OTH exome AF: 0.263

GnomAD4 exome AF: 0.235 AC: 343437 AN: 1461692 Hom.: 43749 Cov.: 37 AF XY: 0.241 AC XY: 175412 AN XY: 727172

Gnomad4 AFR exome AF: 0.276

Gnomad4 AMR exome AF: 0.306

Gnomad4 ASJ exome AF: 0.268

Gnomad4 EAS exome AF: 0.410

Gnomad4 SAS exome AF: 0.428

Gnomad4 FIN exome AF: 0.189

Gnomad4 NFE exome AF: 0.210

Gnomad4 OTH exome AF: 0.252

GnomAD4 genome AF: 0.249 AC: 37852 AN: 152012 Hom.: 5024 Cov.: 31 AF XY: 0.251 AC XY: 18636 AN XY: 74290

Gnomad4 AFR AF: 0.272

Gnomad4 AMR AF: 0.250

Gnomad4 ASJ AF: 0.265

Gnomad4 EAS AF: 0.420

Gnomad4 SAS AF: 0.449

Gnomad4 FIN AF: 0.180

Gnomad4 NFE AF: 0.216

Gnomad4 OTH AF: 0.267

Alfa AF: 0.231 Hom.: 1722

Bravo AF: 0.256

Asia WGS AF: 0.409 AC: 1421 AN: 3478

EpiCase AF: 0.223

EpiControl AF: 0.227

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 3 multiple types Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	4.7
DANN	Benign	0.37

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: rs8140949; hg19: chr22-25627604; COSMIC: COSV68005535;