chr22-25221785-C-G

Position:

• chr22-25221785-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000496.3(CRYBB2):​c.54+302C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0315 in 152,312 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.032 (103 hom., cov: 33)
• Consequence: CRYBB2 NM_000496.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.403

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=-0.86).
• BP6: Variant 22-25221785-C-G is Benign according to our data. Variant chr22-25221785-C-G is described in ClinVar as [Benign]. Clinvar id is 1266097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0315 (4803/152312) while in subpopulation NFE AF= 0.0443 (3014/68020). AF 95% confidence interval is 0.043. There are 103 homozygotes in gnomad4. There are 2435 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4803 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYBB2	NM_000496.3	c.54+302C>G		intron_variant		ENST00000398215.3	NP_000487.1
CRYBB2	XM_006724141.4	c.54+302C>G		intron_variant			XP_006724204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYBB2	ENST00000398215.3	c.54+302C>G		intron_variant		1	NM_000496.3	ENSP00000381273	P1
CRYBB2	ENST00000651629.1	c.54+302C>G		intron_variant				ENSP00000498905	P1

Frequencies

GnomAD3 genomes AF: 0.0316 AC: 4804 AN: 152194 Hom.: 103 Cov.: 33

Gnomad AFR AF: 0.00709

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.0255

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.0800

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0443

Gnomad OTH AF: 0.0311

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0315 AC: 4803 AN: 152312 Hom.: 103 Cov.: 33 AF XY: 0.0327 AC XY: 2435 AN XY: 74482

Gnomad4 AFR AF: 0.00707

Gnomad4 AMR AF: 0.0254

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00622

Gnomad4 FIN AF: 0.0800

Gnomad4 NFE AF: 0.0443

Gnomad4 OTH AF: 0.0308

Alfa AF: 0.0416 Hom.: 17

Bravo AF: 0.0257

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	9.4
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs117091669; hg19: chr22-25617752;