NM_180990.4:c.770G>A

Variant names:

• chr17-76081645-G-A
• rs776661652
• NM_180990.4:c.770G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_180990.4(ZACN):​c.770G>A​(p.Arg257Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000923 in 1,614,018 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000074 (1 hom.)
• Consequence: ZACN NM_180990.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.70

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 17-76081645-G-A is Benign according to our data. Variant chr17-76081645-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3471894.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZACN	NM_180990.4	c.770G>A	p.Arg257Gln	missense_variant	Exon 7 of 9	ENST00000334586.10	NP_851321.2
EXOC7	NM_001013839.4	c.*2003C>T		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.770G>A	p.Arg257Gln	missense_variant	Exon 7 of 9	1	NM_180990.4	ENSP00000334854.5
EXOC7	ENST00000589210	c.*2003C>T		3_prime_UTR_variant	Exon 19 of 19	1	NM_001013839.4	ENSP00000468404.1

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000175 AC: 44 AN: 251188 Hom.: 1 AF XY: 0.000177 AC XY: 24 AN XY: 135788

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000739 AC: 108 AN: 1461780 Hom.: 1 Cov.: 35 AF XY: 0.0000701 AC XY: 51 AN XY: 727178

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.000377 AC XY: 28 AN XY: 74368

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000260 Hom.: 0

Bravo AF: 0.000302

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jul 07, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.54
DANN	Benign	0.85
DEOGEN2	Benign	0.00042	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	-0.090	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.25	N
REVEL	Benign	0.24
Sift	Benign	0.28	T
Sift4G	Benign	0.14	T
Polyphen		0.0030	B
Vest4		0.11
MutPred		0.42		Gain of loop (P = 0.2045);
MVP		0.15
MPC		0.086
ClinPred		0.019	T
GERP RS		-9.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.049
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs776661652; hg19: chr17-74077726; COSMIC: COSV100135183; COSMIC: COSV100135183;