17-76081642-T-C

Variant names:

• chr17-76081642-T-C
• rs1796267489
• NM_180990.4:c.767T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_180990.4(ZACN):​c.767T>C​(p.Leu256Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ZACN NM_180990.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.92

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZACN	NM_180990.4	c.767T>C	p.Leu256Pro	missense_variant	Exon 7 of 9	ENST00000334586.10	NP_851321.2
EXOC7	NM_001013839.4	c.*2006A>G		3_prime_UTR_variant	Exon 19 of 19	ENST00000589210.6	NP_001013861.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZACN	ENST00000334586.10	c.767T>C	p.Leu256Pro	missense_variant	Exon 7 of 9	1	NM_180990.4	ENSP00000334854.5
EXOC7	ENST00000589210	c.*2006A>G		3_prime_UTR_variant	Exon 19 of 19	1	NM_001013839.4	ENSP00000468404.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461782 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 727180

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: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.767T>C (p.L256P) alteration is located in exon 7 (coding exon 7) of the ZACN gene. This alteration results from a T to C substitution at nucleotide position 767, causing the leucine (L) at amino acid position 256 to be replaced by a proline (P). 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	0.12
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.00044	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.091
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.48	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.5	L
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.82	N
REVEL	Uncertain	0.36
Sift	Benign	0.16	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.40
MutPred		0.47		Gain of catalytic residue at P255 (P = 0.0161);
MVP		0.50
MPC		0.51
ClinPred		0.53	D
GERP RS		4.6
Varity_R		0.31
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs1796267489; hg19: chr17-74077723;