NM_001886.3:c.106G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001886.3(CRYBA4):c.106G>A(p.Val36Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0207 in 1,614,012 control chromosomes in the GnomAD database, including 411 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V36V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.017 ( 27 hom., cov: 32)

Exomes 𝑓: 0.021 ( 384 hom. )

Consequence

CRYBA4
NM_001886.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.39

Publications

8 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030172765).

BP6

Variant 22-26623300-G-A is Benign according to our data. Variant chr22-26623300-G-A is described in ClinVar as Benign. ClinVar VariationId is 258485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0166 (2532/152278) while in subpopulation NFE AF = 0.025 (1703/68032). AF 95% confidence interval is 0.024. There are 27 homozygotes in GnomAd4. There are 1220 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 27 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBA4	NM_001886.3 link	c.106G>A	p.Val36Met	missense_variant	Exon 3 of 6	ENST00000354760.4	NP_001877.1
CRYBA4	XM_006724140.4 link	c.121G>A	p.Val41Met	missense_variant	Exon 5 of 8		XP_006724203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYBA4	ENST00000354760.4 link	c.106G>A	p.Val36Met	missense_variant	Exon 3 of 6	1	NM_001886.3	ENSP00000346805.3
CRYBA4	ENST00000466315.1 link	n.55+665G>A		intron_variant	Intron 2 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.0166

AC:

2531

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00471

Gnomad AMI

AF:

0.00659

Gnomad AMR

AF:

0.00700

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00434

Gnomad FIN

AF:

0.0433

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0250

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.0174

AC:

4372

AN:

251340

AF XY:

0.0180

show subpopulations

Gnomad AFR exome

AF:

0.00492

Gnomad AMR exome

AF:

0.00728

Gnomad ASJ exome

AF:

0.00397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0437

Gnomad NFE exome

AF:

0.0250

Gnomad OTH exome

AF:

0.0169

GnomAD4 exome

AF:

0.0212

AC:

30922

AN:

1461734

Hom.:

384

Cov.:

AF XY:

0.0208

AC XY:

15138

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.00320

AC:

107

AN:

33480

American (AMR)

AF:

0.00745

AC:

333

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00578

AC:

151

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00436

AC:

376

AN:

86258

European-Finnish (FIN)

AF:

0.0409

AC:

2181

AN:

53304

Middle Eastern (MID)

AF:

0.0101

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0241

AC:

26802

AN:

1111978

Other (OTH)

AF:

0.0151

AC:

914

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

1645

3290

4935

6580

8225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

962

1924

2886

3848

4810

<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:

0.0166

AC:

2532

AN:

152278

Hom.:

Cov.:

AF XY:

0.0164

AC XY:

1220

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00470

AC:

195

AN:

41532

American (AMR)

AF:

0.00699

AC:

107

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.00435

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0433

AC:

459

AN:

10610

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0250

AC:

1703

AN:

68032

Other (OTH)

AF:

0.0123

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

133

266

398

531

664

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0211

Hom.:

143

Bravo

AF:

0.0139

TwinsUK

AF:

0.0264

AC:

ALSPAC

AF:

0.0213

AC:

ESP6500AA

AF:

0.00885

AC:

ESP6500EA

AF:

0.0248

AC:

213

ExAC

AF:

0.0173

AC:

2100

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0248

EpiControl

AF:

0.0274

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 22, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cataract 23

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.076

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0030

MetaSVM

Benign

-0.33

MutationAssessor

Benign

1.5

PhyloP100

1.4

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.0

REVEL

Benign

0.22

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.032

Polyphen

1.0

Vest4

0.16

MPC

0.88

ClinPred

0.015

GERP RS

3.4

Varity_R

0.40

gMVP

0.57

Mutation Taster

=95/5

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over