22-25201402-G-A

Position:

• chr22-25201402-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004076.5(CRYBB3):​c.6G>A​(p.Ala2=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000774 in 1,613,314 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (5 hom.)
• Consequence: CRYBB3 NM_004076.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.42

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 22-25201402-G-A is Benign according to our data. Variant chr22-25201402-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 703368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-25201402-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.42 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00171 (260/152240) while in subpopulation AFR AF= 0.004 (166/41542). AF 95% confidence interval is 0.0035. There are 0 homozygotes in gnomad4. There are 123 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYBB3	NM_004076.5	c.6G>A	p.Ala2=	synonymous_variant	2/6	ENST00000215855.7
CRYBB3	XM_047441147.1	c.6G>A	p.Ala2=	synonymous_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYBB3	ENST00000215855.7	c.6G>A	p.Ala2=	synonymous_variant	2/6	1	NM_004076.5	P1
CRYBB3	ENST00000404334.1	c.6G>A	p.Ala2=	synonymous_variant	2/5	3

Frequencies

GnomAD3 genomes AF: 0.00170 AC: 259 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00398

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.0185

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00119 AC: 299 AN: 251400 Hom.: 1 AF XY: 0.000993 AC XY: 135 AN XY: 135898

Gnomad AFR exome AF: 0.00400

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.0162

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000343

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000677 AC: 989 AN: 1461074 Hom.: 5 Cov.: 34 AF XY: 0.000654 AC XY: 475 AN XY: 726840

Gnomad4 AFR exome AF: 0.00484

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.0169

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000220

Gnomad4 OTH exome AF: 0.00162

GnomAD4 genome AF: 0.00171 AC: 260 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.00165 AC XY: 123 AN XY: 74428

Gnomad4 AFR AF: 0.00400

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.0185

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00179 Hom.: 1

Bravo AF: 0.00182

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2022

CRYBB3: BP4, BP7 -

Cataract 22 multiple types Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 22, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.25
DANN	Benign	0.78

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: rs144393956; hg19: chr22-25597369;