chr22-25221587-G-C

Position:

• chr22-25221587-G-C

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.54+104G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.044 in 815,004 control chromosomes in the GnomAD database, including 912 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (154 hom., cov: 32)
  • Exomes 𝑓: 0.044 (758 hom.)
• Consequence: CRYBB2 NM_000496.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.64

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=-0.93).
• BP6: Variant 22-25221587-G-C is Benign according to our data. Variant chr22-25221587-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1191251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0845 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYBB2	NM_000496.3	c.54+104G>C		intron_variant		ENST00000398215.3	NP_000487.1
CRYBB2	XM_006724141.4	c.54+104G>C		intron_variant			XP_006724204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYBB2	ENST00000398215.3	c.54+104G>C		intron_variant		1	NM_000496.3	ENSP00000381273	P1
CRYBB2	ENST00000651629.1	c.54+104G>C		intron_variant				ENSP00000498905	P1

Frequencies

GnomAD3 genomes AF: 0.0423 AC: 6438 AN: 152082 Hom.: 153 Cov.: 32

Gnomad AFR AF: 0.0277

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.0371

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.0909

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.0489

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0505

Gnomad OTH AF: 0.0378

GnomAD4 exome AF: 0.0444 AC: 29419 AN: 662804 Hom.: 758 AF XY: 0.0430 AC XY: 15192 AN XY: 352962

Gnomad4 AFR exome AF: 0.0290

Gnomad4 AMR exome AF: 0.0305

Gnomad4 ASJ exome AF: 0.0230

Gnomad4 EAS exome AF: 0.0777

Gnomad4 SAS exome AF: 0.0126

Gnomad4 FIN exome AF: 0.0495

Gnomad4 NFE exome AF: 0.0495

Gnomad4 OTH exome AF: 0.0429

GnomAD4 genome AF: 0.0423 AC: 6445 AN: 152200 Hom.: 154 Cov.: 32 AF XY: 0.0417 AC XY: 3099 AN XY: 74396

Gnomad4 AFR AF: 0.0278

Gnomad4 AMR AF: 0.0370

Gnomad4 ASJ AF: 0.0216

Gnomad4 EAS AF: 0.0913

Gnomad4 SAS AF: 0.0133

Gnomad4 FIN AF: 0.0489

Gnomad4 NFE AF: 0.0505

Gnomad4 OTH AF: 0.0374

Alfa AF: 0.0147 Hom.: 8

Bravo AF: 0.0419

Asia WGS AF: 0.0380 AC: 133 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Likely 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	-0.93
CADD	Benign	0.020
DANN	Benign	0.44

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: rs56191632; hg19: chr22-25617554;