22-25227745-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000496.3(CRYBB2):c.174-108G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0035 in 1,583,688 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (7 hom., cov: 28)
  • Exomes 𝑓: 0.0035 (107 hom.)
• Consequence: CRYBB2 NM_000496.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.323

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 22-25227745-G-A is Benign according to our data. Variant chr22-25227745-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1344953.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0626 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYBB2	NM_000496.3	c.174-108G>A		intron_variant		ENST00000398215.3
CRYBB2	XM_006724141.4	c.174-108G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYBB2	ENST00000398215.3	c.174-108G>A		intron_variant		1	NM_000496.3	P1
CRYBB2	ENST00000651629.1	c.174-108G>A		intron_variant				P1

Frequencies

GnomAD3 genomes AF: 0.00339 AC: 513 AN: 151116 Hom.: 7 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000660

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0497

Gnomad SAS AF: 0.0162

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000678

Gnomad OTH AF: 0.00194

GnomAD4 exome AF: 0.00351 AC: 5032 AN: 1432454 Hom.: 107 AF XY: 0.00379 AC XY: 2707 AN XY: 713764

Gnomad4 AFR exome AF: 0.000121

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00178

Gnomad4 EAS exome AF: 0.0647

Gnomad4 SAS exome AF: 0.0133

Gnomad4 FIN exome AF: 0.00987

Gnomad4 NFE exome AF: 0.000539

Gnomad4 OTH exome AF: 0.00383

GnomAD4 genome AF: 0.00337 AC: 510 AN: 151234 Hom.: 7 Cov.: 28 AF XY: 0.00452 AC XY: 334 AN XY: 73856

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000660

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.0498

Gnomad4 SAS AF: 0.0158

Gnomad4 FIN AF: 0.0119

Gnomad4 NFE AF: 0.000679

Gnomad4 OTH AF: 0.00144

Alfa AF: 0.00127 Hom.: 0

Bravo AF: 0.00228

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 16, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	2.3
Dann	Benign	0.70

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: rs142846156; hg19: chr22-25623712;