1-74719373-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP3 BP6_Very_Strong BS2

The NM_001889.4(CRYZ):c.265-1G>A variant causes a splice acceptor 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
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.13

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]

ACMG classification

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 GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYZ	NM_001889.4	c.265-1G>A		splice_acceptor_variant		ENST00000340866.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYZ	ENST00000340866.10	c.265-1G>A		splice_acceptor_variant		1	NM_001889.4	P1

Frequencies

GnomAD3 genomes AF: 0.000592 AC: 90 AN: 152054 Hom.: 2 Cov.: 32

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.: 2 AF XY: 0.000767 AC XY: 103 AN XY: 134340

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.: 9 Cov.: 31 AF XY: 0.000910 AC XY: 657 AN XY: 722224

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: 90 AN: 152172 Hom.: 2 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74398

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.: 2

Bravo AF: 0.000593

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000791 AC: 96

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000879

EpiControl AF: 0.00143

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CRYZ-related disorder Benign:1

Likely benign, criteria provided, single submitter

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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Pathogenic	0.15
Cadd	Pathogenic	33
Dann	Uncertain	0.99
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D
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

Other links and lift over

dbSNP: rs139734636; hg19: chr1-75185057; COSMIC: COSV61717486;