rs142090709

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_001886.3(CRYBA4):c.40-1G>C variant causes a splice acceptor, intron 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, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 6.83

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

cataract 23
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
cataract - microcornea syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset lamellar cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CRYBA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP6

Variant 22-26623233-G-C is Benign according to our data. Variant chr22-26623233-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 217347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001886.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBA4	NM_001886.3	MANE Select	c.40-1G>C		splice_acceptor intron	N/A	NP_001877.1	A0A097PIJ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBA4	ENST00000354760.4	TSL:1 MANE Select	c.40-1G>C		splice_acceptor intron	N/A	ENSP00000346805.3	P53673
	CRYBA4	ENST00000466315.1	TSL:5	n.55+598G>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00358

AC:

544

AN:

152098

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00334

AC:

836

AN:

250598

AF XY:

0.00333

show subpopulations

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 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.:

Cov.:

AF XY:

0.00537

AC XY:

3897

AN XY:

726342

show subpopulations

African (AFR)

AF:

0.000658

AC:

AN:

33458

American (AMR)

AF:

0.00197

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.000191

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00302

AC:

260

AN:

86222

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

52452

Middle Eastern (MID)

AF:

0.00261

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00659

AC:

7325

AN:

1111098

Other (OTH)

AF:

0.00409

AC:

247

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

363

726

1090

1453

1816

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

264

528

792

1056

1320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00357

AC:

544

AN:

152216

Hom.:

Cov.:

AF XY:

0.00313

AC XY:

233

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.00113

AC:

AN:

41536

American (AMR)

AF:

0.00262

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00332

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000850

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00628

AC:

427

AN:

67996

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

111

139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00541

Hom.:

Bravo

AF:

0.00356

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00547

AC:

ExAC

AF:

0.00323

AC:

392

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00622

EpiControl

AF:

0.00545

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cataract 23 (2)

not provided (2)

Developmental cataract (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.0076

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

PhyloP100

6.8

GERP RS

4.5

Mutation Taster

=72/28

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over