17-29250258-G-A

Position:

chr17-29250258-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 2P and 14B. PM1BP4_StrongBP6_ModerateBS1BS2

The NM_005208.5(CRYBA1):c.173G>A(p.Arg58His) variant causes a missense change. The variant allele was found at a frequency of 0.00171 in 1,613,392 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00089 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 4 hom. )

Consequence

CRYBA1
NM_005208.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 4.60

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 -12 ACMG points.

PM1

In a chain Beta-crystallin A3, isoform A1, Delta7 form (size 189) 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=0.023651779).

BP6

Variant 17-29250258-G-A is Benign according to our data. Variant chr17-29250258-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1571486.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-29250258-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000887 (135/152280) while in subpopulation NFE AF= 0.00163 (111/68020). AF 95% confidence interval is 0.00139. There are 0 homozygotes in gnomad4. There are 60 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 135 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYBA1	NM_005208.5 linkuse as main transcript	c.173G>A	p.Arg58His	missense_variant	3/6	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.173G>A	p.Arg58His	missense_variant	3/6	1	NM_005208.5	ENSP00000225387	P1	P05813-1
CRYBA1	ENST00000484605.1 linkuse as main transcript	c.164G>A	p.Arg55His	missense_variant, NMD_transcript_variant	3/5	5		ENSP00000464368

Frequencies

GnomAD3 genomes

AF:

0.000887

AC:

135

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00163

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00106

AC:

267

AN:

251496

Hom.:

AF XY:

0.00110

AC XY:

149

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.00206

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00179

AC:

2621

AN:

1461112

Hom.:

Cov.:

AF XY:

0.00174

AC XY:

1268

AN XY:

726934

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000449

Gnomad4 NFE exome

AF:

0.00225

Gnomad4 OTH exome

AF:

0.00119

GnomAD4 genome

AF:

0.000887

AC:

135

AN:

152280

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00163

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00145

Hom.:

Bravo

AF:

0.000888

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00114

AC:

139

EpiCase

AF:

0.00174

EpiControl

AF:

0.00142

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

CRYBA1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cataract 10 multiple types

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.54

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.095

M_CAP

Benign

0.038

MetaRNN

Benign

0.024

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.4

MutationTaster

Benign

0.87

PrimateAI

Benign

0.30

PROVEAN

Benign

-2.3

REVEL

Benign

0.18

Sift

Benign

0.56

Sift4G

Benign

0.55

Polyphen

0.18

Vest4

0.24

MVP

0.82

MPC

0.37

ClinPred

0.077

GERP RS

2.9

Varity_R

0.079

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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