chr22-26625493-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000354760.4(CRYBA4):c.171T>C(p.Phe57Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.86 in 1,613,620 control chromosomes in the GnomAD database, including 598,763 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.89 ( 60204 hom., cov: 31)

Exomes 𝑓: 0.86 ( 538559 hom. )

Consequence

CRYBA4
ENST00000354760.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.258

Publications

27 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: Labcorp Genetics (formerly Invitae), G2P, 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 22-26625493-T-C is Benign according to our data. Variant chr22-26625493-T-C is described in ClinVar as Benign. ClinVar VariationId is 258487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.258 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.972 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000354760.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBA4	NM_001886.3	MANE Select	c.171T>C	p.Phe57Phe	synonymous	Exon 4 of 6	NP_001877.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBA4	ENST00000354760.4	TSL:1 MANE Select	c.171T>C	p.Phe57Phe	synonymous	Exon 4 of 6	ENSP00000346805.3
	CRYBA4	ENST00000466315.1	TSL:5	n.68T>C		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes

AF:

0.888

AC:

135059

AN:

152098

Hom.:

60146

Cov.:

show subpopulations

Gnomad AFR

AF:

0.924

Gnomad AMI

AF:

0.803

Gnomad AMR

AF:

0.900

Gnomad ASJ

AF:

0.936

Gnomad EAS

AF:

0.995

Gnomad SAS

AF:

0.924

Gnomad FIN

AF:

0.925

Gnomad MID

AF:

0.886

Gnomad NFE

AF:

0.845

Gnomad OTH

AF:

0.908

GnomAD2 exomes

AF:

0.896

AC:

225031

AN:

251174

AF XY:

0.894

show subpopulations

Gnomad AFR exome

AF:

0.928

Gnomad AMR exome

AF:

0.943

Gnomad ASJ exome

AF:

0.931

Gnomad EAS exome

AF:

0.997

Gnomad FIN exome

AF:

0.924

Gnomad NFE exome

AF:

0.846

Gnomad OTH exome

AF:

0.883

GnomAD4 exome

AF:

0.857

AC:

1252929

AN:

1461404

Hom.:

538559

Cov.:

AF XY:

0.859

AC XY:

624329

AN XY:

726998

show subpopulations

African (AFR)

AF:

0.927

AC:

31018

AN:

33478

American (AMR)

AF:

0.939

AC:

41971

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.933

AC:

24391

AN:

26134

East Asian (EAS)

AF:

0.998

AC:

39611

AN:

39700

South Asian (SAS)

AF:

0.921

AC:

79444

AN:

86254

European-Finnish (FIN)

AF:

0.917

AC:

48790

AN:

53196

Middle Eastern (MID)

AF:

0.895

AC:

5161

AN:

5768

European-Non Finnish (NFE)

AF:

0.836

AC:

929720

AN:

1111778

Other (OTH)

AF:

0.875

AC:

52823

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

9324

18648

27973

37297

46621

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21106

42212

63318

84424

105530

<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:

0.888

AC:

135177

AN:

152216

Hom.:

60204

Cov.:

AF XY:

0.892

AC XY:

66417

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.924

AC:

38372

AN:

41542

American (AMR)

AF:

0.900

AC:

13771

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.936

AC:

3248

AN:

3470

East Asian (EAS)

AF:

0.995

AC:

5142

AN:

5168

South Asian (SAS)

AF:

0.924

AC:

4454

AN:

4818

European-Finnish (FIN)

AF:

0.925

AC:

9821

AN:

10614

Middle Eastern (MID)

AF:

0.891

AC:

262

AN:

294

European-Non Finnish (NFE)

AF:

0.845

AC:

57457

AN:

67992

Other (OTH)

AF:

0.909

AC:

1919

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

753

1506

2259

3012

3765

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

900

1800

2700

3600

4500

<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:

0.864

Hom.:

30010

Bravo

AF:

0.889

Asia WGS

AF:

0.956

AC:

3323

AN:

3478

EpiCase

AF:

0.852

EpiControl

AF:

0.853

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cataract 23 (2)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

2.0

(source)

DANN

Benign

0.62

PhyloP100

0.26

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over