22-25201364-T-C

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.-20-13T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.539 in 1,611,378 control chromosomes in the GnomAD database, including 238,312 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (28865 hom., cov: 32)
  • Exomes 𝑓: 0.53 (209447 hom.)
• Consequence: CRYBB3 NM_004076.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.341

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 (BayesDel_noAF=-0.92).
• BP6: Variant 22-25201364-T-C is Benign according to our data. Variant chr22-25201364-T-C is described in ClinVar as [Benign]. Clinvar id is 340947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYBB3	NM_004076.5	c.-20-13T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000215855.7
CRYBB3	XM_047441147.1	c.-33T>C		5_prime_UTR_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYBB3	ENST00000215855.7	c.-20-13T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_004076.5	P1
CRYBB3	ENST00000404334.1	c.-16-17T>C		splice_polypyrimidine_tract_variant, intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.603 AC: 91641 AN: 151984 Hom.: 28801 Cov.: 32

Gnomad AFR AF: 0.787

Gnomad AMI AF: 0.503

Gnomad AMR AF: 0.598

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.684

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.469

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.515

Gnomad OTH AF: 0.595

GnomAD3 exomes AF: 0.564 AC: 141604 AN: 251264 Hom.: 40931 AF XY: 0.553 AC XY: 75141 AN XY: 135836

Gnomad AFR exome AF: 0.788

Gnomad AMR exome AF: 0.647

Gnomad ASJ exome AF: 0.565

Gnomad EAS exome AF: 0.683

Gnomad SAS exome AF: 0.525

Gnomad FIN exome AF: 0.472

Gnomad NFE exome AF: 0.514

Gnomad OTH exome AF: 0.560

GnomAD4 exome AF: 0.532 AC: 777059 AN: 1459276 Hom.: 209447 Cov.: 107 AF XY: 0.531 AC XY: 385342 AN XY: 725938

Gnomad4 AFR exome AF: 0.800

Gnomad4 AMR exome AF: 0.641

Gnomad4 ASJ exome AF: 0.569

Gnomad4 EAS exome AF: 0.660

Gnomad4 SAS exome AF: 0.523

Gnomad4 FIN exome AF: 0.471

Gnomad4 NFE exome AF: 0.517

Gnomad4 OTH exome AF: 0.557

GnomAD4 genome AF: 0.603 AC: 91761 AN: 152102 Hom.: 28865 Cov.: 32 AF XY: 0.602 AC XY: 44781 AN XY: 74350

Gnomad4 AFR AF: 0.788

Gnomad4 AMR AF: 0.598

Gnomad4 ASJ AF: 0.563

Gnomad4 EAS AF: 0.684

Gnomad4 SAS AF: 0.536

Gnomad4 FIN AF: 0.469

Gnomad4 NFE AF: 0.515

Gnomad4 OTH AF: 0.600

Alfa AF: 0.534 Hom.: 27691

Bravo AF: 0.628

Asia WGS AF: 0.645 AC: 2244 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital nuclear cataract Benign:1

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

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. -

Cataract 22 multiple types Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	8.8
Dann	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2269672; hg19: chr22-25597331; COSMIC: COSV53194219; COSMIC: COSV53194219;