NM_005208.5:c.74C>T

Variant names:

Variant summary

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

The NM_005208.5(CRYBA1):c.74C>T(p.Pro25Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0258 in 1,612,402 control chromosomes in the GnomAD database, including 651 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P25P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.019 ( 36 hom., cov: 31)

Exomes 𝑓: 0.027 ( 615 hom. )

Consequence

CRYBA1
NM_005208.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.18

Publications

6 publications found

Variant links:

Genes affected

CRYBA1 (HGNC:2394): (crystallin beta A1) 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, encodes two proteins (crystallin, beta A3 and crystallin, beta A1) from a single mRNA, the latter protein is 17 aa shorter than crystallin, beta A3 and is generated by use of an alternate translation initiation site. Deletion of exons 3 and 4 causes the autosomal dominant disease 'zonular cataract with sutural opacities'. [provided by RefSeq, Jul 2008]

CRYBA1 Gene-Disease associations (from GenCC):

cataract 10 multiple types
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
early-onset lamellar cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset nuclear cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset posterior polar cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset sutural cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CRYBA1 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=0.0055909455).

BP6

Variant 17-29249184-C-T is Benign according to our data. Variant chr17-29249184-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 259673.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 = 0.0186 (2837/152200) while in subpopulation NFE AF = 0.0298 (2028/67998). AF 95% confidence interval is 0.0287. There are 36 homozygotes in GnomAd4. There are 1311 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 2837 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBA1	NM_005208.5 link	c.74C>T	p.Pro25Leu	missense_variant	Exon 2 of 6	ENST00000225387.8	NP_005199.2	P05813-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYBA1	ENST00000225387.8 link	c.74C>T	p.Pro25Leu	missense_variant	Exon 2 of 6	1	NM_005208.5	ENSP00000225387.3		P05813-1
CRYBA1	ENST00000484605.1 link	n.62C>T		non_coding_transcript_exon_variant	Exon 2 of 5	5		ENSP00000464368.1		J3QRT1

Frequencies

GnomAD3 genomes

AF:

0.0187

AC:

2838

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00565

Gnomad AMI

AF:

0.0318

Gnomad AMR

AF:

0.0119

Gnomad ASJ

AF:

0.0164

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00270

Gnomad FIN

AF:

0.0246

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0298

Gnomad OTH

AF:

0.0153

GnomAD2 exomes

AF:

0.0172

AC:

4326

AN:

251296

AF XY:

0.0175

show subpopulations

Gnomad AFR exome

AF:

0.00512

Gnomad AMR exome

AF:

0.00824

Gnomad ASJ exome

AF:

0.0145

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0214

Gnomad NFE exome

AF:

0.0273

Gnomad OTH exome

AF:

0.0166

GnomAD4 exome

AF:

0.0266

AC:

38835

AN:

1460202

Hom.:

615

Cov.:

AF XY:

0.0257

AC XY:

18666

AN XY:

726520

show subpopulations

African (AFR)

AF:

0.00418

AC:

140

AN:

33462

American (AMR)

AF:

0.00870

AC:

389

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0138

AC:

361

AN:

26124

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39696

South Asian (SAS)

AF:

0.00467

AC:

403

AN:

86238

European-Finnish (FIN)

AF:

0.0221

AC:

1179

AN:

53402

Middle Eastern (MID)

AF:

0.00451

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0314

AC:

34869

AN:

1110480

Other (OTH)

AF:

0.0243

AC:

1465

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

1620

3240

4861

6481

8101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0186

AC:

2837

AN:

152200

Hom.:

Cov.:

AF XY:

0.0176

AC XY:

1311

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.00563

AC:

234

AN:

41556

American (AMR)

AF:

0.0118

AC:

181

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0164

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.00270

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.0246

AC:

261

AN:

10594

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0298

AC:

2028

AN:

67998

Other (OTH)

AF:

0.0152

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

137

274

411

548

685

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0252

Hom.:

186

Bravo

AF:

0.0177

TwinsUK

AF:

0.0310

AC:

115

ALSPAC

AF:

0.0330

AC:

127

ESP6500AA

AF:

0.00681

AC:

ESP6500EA

AF:

0.0270

AC:

232

ExAC

AF:

0.0172

AC:

2088

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0249

EpiControl

AF:

0.0244

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 03, 2024

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cataract 10 multiple types

Benign:1

Jan 20, 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

0.081

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.15

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.49

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0056

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

PhyloP100

2.2

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.2

REVEL

Benign

0.16

Sift

Uncertain

0.027

Sift4G

Benign

0.21

Polyphen

0.30

Vest4

0.20

MPC

0.32

ClinPred

0.022

GERP RS

3.7

Varity_R

0.075

gMVP

0.35

Mutation Taster

=90/10

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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NM_005208.5:c.74C>T

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