22-26623233-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001886.3(CRYBA4):c.40-1G>C variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00532 in 1,612,052 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (32 hom.)
• Consequence: CRYBA4 NM_001886.3 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.83

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 Likely_benign. Variant got -3 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 5: BayesDel_noAF, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, Eigen [when BayesDel_addAF, MutationTaster was below the threshold]
• BS2: High AC in GnomAd at 544 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYBA4	NM_001886.3	c.40-1G>C		splice_acceptor_variant		ENST00000354760.4
CRYBA4	XM_006724140.4	c.55-1G>C		splice_acceptor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYBA4	ENST00000354760.4	c.40-1G>C		splice_acceptor_variant		1	NM_001886.3	P1
CRYBA4	ENST00000466315.1	n.55+598G>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00358 AC: 544 AN: 152098 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.000850

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00628

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00334 AC: 836 AN: 250598 Hom.: 5 AF XY: 0.00333 AC XY: 451 AN XY: 135500

Gnomad AFR exome AF: 0.000989

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00235

Gnomad FIN exome AF: 0.00124

Gnomad NFE exome AF: 0.00556

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00550 AC: 8026 AN: 1459836 Hom.: 32 Cov.: 32 AF XY: 0.00537 AC XY: 3897 AN XY: 726342

Gnomad4 AFR exome AF: 0.000658

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00302

Gnomad4 FIN exome AF: 0.00122

Gnomad4 NFE exome AF: 0.00659

Gnomad4 OTH exome AF: 0.00409

GnomAD4 genome AF: 0.00357 AC: 544 AN: 152216 Hom.: 3 Cov.: 32 AF XY: 0.00313 AC XY: 233 AN XY: 74420

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.000850

Gnomad4 NFE AF: 0.00628

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00541 Hom.: 1

Bravo AF: 0.00356

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.00323 AC: 392

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00622

EpiControl AF: 0.00545

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 27, 2019	This variant is associated with the following publications: (PMID: 26694549) -

Cataract 23 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 09, 2024

- -

Developmental cataract Benign:1

Benign, no assertion criteria provided

research

Eye Genetics Research Group, Children's Medical Research Institute

Jan 09, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.0076	T
BayesDel_noAF	Pathogenic	0.22
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D
GERP RS		4.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs142090709; hg19: chr22-27019197; COSMIC: COSV61322427;