Variant chr1-74719373-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP3BP6_Very_StrongBS2

The NM_001889.4(CRYZ):c.265-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000929 in 1,606,500 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00059 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00096 ( 9 hom. )

Consequence

CRYZ
NM_001889.4 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 7.13

Variant links:

Genes affected

CRYZ (HGNC:2419): (crystallin zeta) 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. The former class is also called phylogenetically-restricted crystallins. This gene encodes a taxon-specific crystallin protein which has NADPH-dependent quinone reductase activity distinct from other known quinone reductases. It lacks alcohol dehydrogenase activity although by similarity it is considered a member of the zinc-containing alcohol dehydrogenase family. Unlike other mammalian species, in humans, lens expression is low. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. One pseudogene is known to exist. [provided by RefSeq, Sep 2008]

CRYZ links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 6: BayesDel_noAF, Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, Eigen [when BayesDel_addAF, MutationTaster was below the threshold]

BP6

Variant 1-74719373-C-T is Benign according to our data. Variant chr1-74719373-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 771689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYZ	NM_001889.4 link	c.265-1G>A		splice_acceptor_variant, intron_variant		ENST00000340866.10	NP_001880.2	Q08257-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYZ	ENST00000340866.10 link	c.265-1G>A		splice_acceptor_variant, intron_variant		1	NM_001889.4	ENSP00000339399.5		Q08257-1

Frequencies

GnomAD3 genomes

AF:

0.000592

AC:

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00107

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000768

AC:

191

AN:

248668

Hom.:

AF XY:

0.000767

AC XY:

103

AN XY:

134340

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.000235

Gnomad ASJ exome

AF:

0.00293

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000132

Gnomad FIN exome

AF:

0.000326

Gnomad NFE exome

AF:

0.00121

Gnomad OTH exome

AF:

0.000993

GnomAD4 exome

AF:

0.000964

AC:

1402

AN:

1454328

Hom.:

Cov.:

AF XY:

0.000910

AC XY:

657

AN XY:

722224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000600

Gnomad4 AMR exome

AF:

0.000271

Gnomad4 ASJ exome

AF:

0.00216

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000105

Gnomad4 FIN exome

AF:

0.000394

Gnomad4 NFE exome

AF:

0.00110

Gnomad4 OTH exome

AF:

0.00115

GnomAD4 genome

AF:

0.000591

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00107

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00104

Hom.:

Bravo

AF:

0.000593

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000791

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000879

EpiControl

AF:

0.00143

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

CRYZ-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 11, 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.034

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

1.0

GERP RS

5.2

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.90

SpliceAI score (max)

0.97

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.57

Position offset: -5

DS_AL_spliceai

0.97

Position offset: -1

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