chr17-76082538-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_180990.4(ZACN):ā€‹c.1124T>Cā€‹(p.Val375Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,544 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

ZACN
NM_180990.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.615
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.10611516).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZACNNM_180990.4 linkc.1124T>C p.Val375Ala missense_variant Exon 9 of 9 ENST00000334586.10 NP_851321.2 Q401N2-1
EXOC7NM_001013839.4 linkc.*1110A>G 3_prime_UTR_variant Exon 19 of 19 ENST00000589210.6 NP_001013861.1 Q9UPT5-1Q63HP7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZACNENST00000334586.10 linkc.1124T>C p.Val375Ala missense_variant Exon 9 of 9 1 NM_180990.4 ENSP00000334854.5 Q401N2-1
EXOC7ENST00000589210 linkc.*1110A>G 3_prime_UTR_variant Exon 19 of 19 1 NM_001013839.4 ENSP00000468404.1 Q9UPT5-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461544
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727104
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Nov 07, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1124T>C (p.V375A) alteration is located in exon 9 (coding exon 9) of the ZACN gene. This alteration results from a T to C substitution at nucleotide position 1124, causing the valine (V) at amino acid position 375 to be replaced by an alanine (A). 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
0.10
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
14
DANN
Benign
0.74
DEOGEN2
Benign
0.0095
T
Eigen
Benign
-0.62
Eigen_PC
Benign
-0.63
FATHMM_MKL
Benign
0.40
N
LIST_S2
Benign
0.41
T
M_CAP
Benign
0.0055
T
MetaRNN
Benign
0.11
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.1
L
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-1.8
N
REVEL
Benign
0.017
Sift
Benign
0.18
T
Sift4G
Pathogenic
0.0
D
Polyphen
0.23
B
Vest4
0.27
MutPred
0.33
Loss of stability (P = 0.0204);
MVP
0.030
MPC
0.13
ClinPred
0.11
T
GERP RS
1.7
Varity_R
0.076
gMVP
0.28

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs2067027082; hg19: chr17-74078619; API