Genetic Variant CRYBA4:c.40-70C>T (chr22-26623164-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.166

Variant links:

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]

CRYBA4 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
CRYBA4	NM_001886.3 link	c.40-70C>T		intron_variant	Intron 2 of 5	ENST00000354760.4	NP_001877.1	P53673A0A097PIJ6
CRYBA4	XM_006724140.4 link	c.55-70C>T		intron_variant	Intron 4 of 7		XP_006724203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYBA4	ENST00000354760.4 link	c.40-70C>T		intron_variant	Intron 2 of 5	1	NM_001886.3	ENSP00000346805.3		P53673
CRYBA4	ENST00000466315.1 link	n.55+529C>T		intron_variant	Intron 2 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.333

AC:

50646

AN:

151940

Hom.:

9042

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.336

AC XY:

24961

AN XY:

74324

show subpopulations

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:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over