rs4049505

Positions:

• chr22-25229587-G-A
• chr22-25229587-G-T

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.449+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.691 in 1,613,564 control chromosomes in the GnomAD database, including 388,526 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (39477 hom., cov: 35)
  • Exomes 𝑓: 0.69 (349049 hom.)
• Consequence: CRYBB2 NM_000496.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.60

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=-0.87).
• BP6: Variant 22-25229587-G-A is Benign according to our data. Variant chr22-25229587-G-A is described in ClinVar as [Benign]. Clinvar id is 256282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-25229587-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.936 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYBB2	NM_000496.3	c.449+9G>A		intron_variant		ENST00000398215.3	NP_000487.1
CRYBB2	XM_006724141.4	c.449+9G>A		intron_variant			XP_006724204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYBB2	ENST00000398215.3	c.449+9G>A		intron_variant		1	NM_000496.3	ENSP00000381273	P1
CRYBB2	ENST00000651629.1	c.449+9G>A		intron_variant				ENSP00000498905	P1

Frequencies

GnomAD3 genomes AF: 0.716 AC: 108986 AN: 152134 Hom.: 39456 Cov.: 35

Gnomad AFR AF: 0.783

Gnomad AMI AF: 0.700

Gnomad AMR AF: 0.699

Gnomad ASJ AF: 0.672

Gnomad EAS AF: 0.958

Gnomad SAS AF: 0.803

Gnomad FIN AF: 0.645

Gnomad MID AF: 0.764

Gnomad NFE AF: 0.668

Gnomad OTH AF: 0.726

GnomAD3 exomes AF: 0.726 AC: 181914 AN: 250512 Hom.: 67153 AF XY: 0.724 AC XY: 98108 AN XY: 135420

Gnomad AFR exome AF: 0.787

Gnomad AMR exome AF: 0.777

Gnomad ASJ exome AF: 0.682

Gnomad EAS exome AF: 0.956

Gnomad SAS exome AF: 0.786

Gnomad FIN exome AF: 0.653

Gnomad NFE exome AF: 0.668

Gnomad OTH exome AF: 0.694

GnomAD4 exome AF: 0.688 AC: 1005378 AN: 1461312 Hom.: 349049 Cov.: 69 AF XY: 0.691 AC XY: 502014 AN XY: 726946

Gnomad4 AFR exome AF: 0.787

Gnomad4 AMR exome AF: 0.769

Gnomad4 ASJ exome AF: 0.679

Gnomad4 EAS exome AF: 0.961

Gnomad4 SAS exome AF: 0.783

Gnomad4 FIN exome AF: 0.649

Gnomad4 NFE exome AF: 0.665

Gnomad4 OTH exome AF: 0.704

GnomAD4 genome AF: 0.716 AC: 109059 AN: 152252 Hom.: 39477 Cov.: 35 AF XY: 0.716 AC XY: 53306 AN XY: 74450

Gnomad4 AFR AF: 0.783

Gnomad4 AMR AF: 0.699

Gnomad4 ASJ AF: 0.672

Gnomad4 EAS AF: 0.958

Gnomad4 SAS AF: 0.802

Gnomad4 FIN AF: 0.645

Gnomad4 NFE AF: 0.668

Gnomad4 OTH AF: 0.728

Alfa AF: 0.692 Hom.: 15768

Bravo AF: 0.728

Asia WGS AF: 0.859 AC: 2988 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 3 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 26, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.12
DANN	Benign	0.63

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: rs4049505; hg19: chr22-25625554;