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GeneBe

17-76081695-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_180990.4(ZACN):​c.820G>A​(p.Val274Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

ZACN
NM_180990.4 missense

Scores

1
7
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.82
Variant links:
Genes affected
ZACN (HGNC:29504): (zinc activated ion channel) LGICZ1 is a zinc-activated ligand-gated ion channel that defines a new subgroup of the cysteine-loop superfamily of ligand-gated ion channels (Davies et al., 2003 [PubMed 12381728]).[supplied by OMIM, Mar 2008]
EXOC7 (HGNC:23214): (exocyst complex component 7) The protein encoded by this gene is a component of the exocyst complex. The exocyst complex plays a critical role in vesicular trafficking and the secretory pathway by targeting post-Golgi vesicles to the plasma membrane. The encoded protein is required for assembly of the exocyst complex and docking of the complex to the plasma membrane. The encoded protein may also play a role in pre-mRNA splicing through interactions with pre-mRNA-processing factor 19. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 4. [provided by RefSeq, Nov 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3485904).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ZACNNM_180990.4 linkuse as main transcriptc.820G>A p.Val274Ile missense_variant 7/9 ENST00000334586.10
EXOC7NM_001013839.4 linkuse as main transcriptc.*1953C>T 3_prime_UTR_variant 19/19 ENST00000589210.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ZACNENST00000334586.10 linkuse as main transcriptc.820G>A p.Val274Ile missense_variant 7/91 NM_180990.4 P1Q401N2-1
EXOC7ENST00000589210.6 linkuse as main transcriptc.*1953C>T 3_prime_UTR_variant 19/191 NM_001013839.4 Q9UPT5-1

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152140
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000517
AC:
13
AN:
251376
Hom.:
0
AF XY:
0.0000589
AC XY:
8
AN XY:
135886
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000163
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000246
AC:
36
AN:
1461812
Hom.:
0
Cov.:
34
AF XY:
0.0000303
AC XY:
22
AN XY:
727208
show subpopulations
Gnomad4 AFR exome
AF:
0.000209
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000144
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.000105
AC:
16
AN:
152258
Hom.:
0
Cov.:
33
AF XY:
0.000161
AC XY:
12
AN XY:
74442
show subpopulations
Gnomad4 AFR
AF:
0.000289
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000102
Hom.:
0
Bravo
AF:
0.0000831
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000577
AC:
7
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 07, 2023The c.820G>A (p.V274I) alteration is located in exon 7 (coding exon 7) of the ZACN gene. This alteration results from a G to A substitution at nucleotide position 820, causing the valine (V) at amino acid position 274 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Benign
-0.12
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.0094
T
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Benign
0.68
D
LIST_S2
Benign
0.62
T
M_CAP
Uncertain
0.18
D
MetaRNN
Benign
0.35
T
MetaSVM
Uncertain
0.64
D
MutationAssessor
Uncertain
2.7
M
MutationTaster
Benign
1.0
D;D;N
PrimateAI
Benign
0.48
T
PROVEAN
Benign
-0.91
N
REVEL
Uncertain
0.46
Sift
Benign
0.038
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.36
MVP
0.24
MPC
0.39
ClinPred
0.23
T
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
3.0
Varity_R
0.14
gMVP
0.25

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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.

Other links and lift over

dbSNP: rs375080677; hg19: chr17-74077776; API