17-29249184-C-T

Position:

chr17-29249184-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a chain Beta-crystallin A3 (size 214) in uniprot entity CRBA1_HUMAN there are 7 pathogenic changes around while only 3 benign (70%) in NM_005208.5

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. Variant chr17-29249184-C-T is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2837 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYBA1	NM_005208.5 linkuse as main transcript	c.74C>T	p.Pro25Leu	missense_variant	2/6	ENST00000225387.8	NP_005199.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYBA1	ENST00000225387.8 linkuse as main transcript	c.74C>T	p.Pro25Leu	missense_variant	2/6	1	NM_005208.5	ENSP00000225387	P1	P05813-1
CRYBA1	ENST00000484605.1 linkuse as main transcript	c.65C>T	p.Pro22Leu	missense_variant, NMD_transcript_variant	2/5	5		ENSP00000464368

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

GnomAD3 exomes

AF:

0.0172

AC:

4326

AN:

251296

Hom.:

AF XY:

0.0175

AC XY:

2379

AN XY:

135852

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 SAS exome

AF:

0.00470

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

Gnomad4 AFR exome

AF:

0.00418

Gnomad4 AMR exome

AF:

0.00870

Gnomad4 ASJ exome

AF:

0.0138

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00467

Gnomad4 FIN exome

AF:

0.0221

Gnomad4 NFE exome

AF:

0.0314

Gnomad4 OTH exome

AF:

0.0243

GnomAD4 genome

AF:

0.0186

AC:

2837

AN:

152200

Hom.:

Cov.:

AF XY:

0.0176

AC XY:

1311

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.00563

Gnomad4 AMR

AF:

0.0118

Gnomad4 ASJ

AF:

0.0164

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00270

Gnomad4 FIN

AF:

0.0246

Gnomad4 NFE

AF:

0.0298

Gnomad4 OTH

AF:

0.0152

Alfa

AF:

0.0246

Hom.:

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

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2023	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Cataract 10 multiple types

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

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

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

MutationTaster

Benign

1.0

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over