22-26623164-C-T

Variant summary

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

The NM_001886.3(CRYBA4):c.40-70C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 1,294,130 control chromosomes in the GnomAD database, including 92,227 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.33 (9051 hom., cov: 32)
  • Exomes 𝑓: 0.38 (83176 hom.)
• Consequence: CRYBA4 NM_001886.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.166

Genes affected

CRYBA4 (HGNC:2396): (crystallin beta A4) 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 acidic group member, is part of a gene cluster with beta-B1, beta-B2, and beta-B3. [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 22-26623164-C-T is Benign according to our data. Variant chr22-26623164-C-T is described in ClinVar as [Benign]. Clinvar id is 677163.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYBA4	NM_001886.3	c.40-70C>T		intron_variant		ENST00000354760.4
CRYBA4	XM_006724140.4	c.55-70C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYBA4	ENST00000354760.4	c.40-70C>T		intron_variant		1	NM_001886.3	P1
CRYBA4	ENST00000466315.1	n.55+529C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.333 AC: 50646 AN: 151940 Hom.: 9042 Cov.: 32

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.441

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.368

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.357

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.387

GnomAD4 exome AF: 0.377 AC: 430201 AN: 1142072 Hom.: 83176 AF XY: 0.378 AC XY: 220529 AN XY: 583044

Gnomad4 AFR exome AF: 0.198

Gnomad4 AMR exome AF: 0.565

Gnomad4 ASJ exome AF: 0.419

Gnomad4 EAS exome AF: 0.377

Gnomad4 SAS exome AF: 0.442

Gnomad4 FIN exome AF: 0.344

Gnomad4 NFE exome AF: 0.367

Gnomad4 OTH exome AF: 0.369

GnomAD4 genome AF: 0.333 AC: 50696 AN: 152058 Hom.: 9051 Cov.: 32 AF XY: 0.336 AC XY: 24961 AN XY: 74324

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.441

Gnomad4 ASJ AF: 0.422

Gnomad4 EAS AF: 0.368

Gnomad4 SAS AF: 0.435

Gnomad4 FIN AF: 0.357

Gnomad4 NFE AF: 0.365

Gnomad4 OTH AF: 0.389

Alfa AF: 0.376 Hom.: 21800

Bravo AF: 0.338

Asia WGS AF: 0.411 AC: 1431 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	1.3
Dann	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2071860; hg19: chr22-27019128; COSMIC: COSV61322384;