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1-74707102-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PVS1_StrongPM2BP6_Moderate

The NM_001889.4(CRYZ):c.732+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.000281 in 1,553,570 control chromosomes in the GnomAD database, including 1 homozygotes. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

CRYZ
NM_001889.4 splice_donor

Scores

4
2
1
Splicing: ADA: 0.9999
2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.19
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PVS1
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.102020204 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 1-74707102-C-T is Benign according to our data. Variant chr1-74707102-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 728987.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CRYZNM_001889.4 linkuse as main transcriptc.732+1G>A splice_donor_variant ENST00000340866.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CRYZENST00000340866.10 linkuse as main transcriptc.732+1G>A splice_donor_variant 1 NM_001889.4 P1Q08257-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00146
AC:
221
AN:
151224
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00517
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000264
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00144
GnomAD3 exomes
AF:
0.000377
AC:
85
AN:
225240
Hom.:
0
AF XY:
0.000205
AC XY:
25
AN XY:
122122
show subpopulations
Gnomad AFR exome
AF:
0.00520
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000189
GnomAD4 exome
AF:
0.000153
AC:
214
AN:
1402272
Hom.:
0
Cov.:
26
AF XY:
0.000116
AC XY:
81
AN XY:
699068
show subpopulations
Gnomad4 AFR exome
AF:
0.00592
Gnomad4 AMR exome
AF:
0.000135
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000125
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000186
Gnomad4 OTH exome
AF:
0.000396
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00147
AC:
223
AN:
151298
Hom.:
1
Cov.:
32
AF XY:
0.00131
AC XY:
97
AN XY:
73842
show subpopulations
Gnomad4 AFR
AF:
0.00521
Gnomad4 AMR
AF:
0.000263
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00143
Alfa
AF:
0.000827
Hom.:
0
Bravo
AF:
0.00186
ESP6500AA
AF:
0.00591
AC:
26
ESP6500EA
AF:
0.00
AC:
0
ExAC
?
    Exome Aggregation Consortium database
AF:
0.000494
AC:
60

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeJul 23, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.044
T
BayesDel_noAF
Pathogenic
0.29
Cadd
Uncertain
25
Dann
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Pathogenic
0.98
D
MutationTaster
Benign
1.0
D;D;D;D
GERP RS
5.5

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.95
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.99
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.

Other links and lift over

dbSNP: rs6668086; hg19: chr1-75172786; API