8-109974376-C-T

Position:

• chr8-109974376-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014379.4(KCNV1):​c.13G>A​(p.Gly5Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000223 in 1,344,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: KCNV1 NM_014379.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.35

Genes affected

KCNV1 (HGNC:18861): (potassium voltage-gated channel modifier subfamily V member 1) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium voltage-gated channel subfamily V. This protein is essentially present in the brain, and its role might be to inhibit the function of a particular class of outward rectifier potassium channel types. [provided by RefSeq, Jul 2008]

ENSG00000255402 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041661233).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNV1	NM_014379.4	c.13G>A	p.Gly5Ser	missense_variant	2/4	ENST00000524391.6	NP_055194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNV1	ENST00000524391.6	c.13G>A	p.Gly5Ser	missense_variant	2/4	1	NM_014379.4	ENSP00000435954.1
KCNV1	ENST00000297404.1	c.13G>A	p.Gly5Ser	missense_variant	1/3	1		ENSP00000297404.1
ENSG00000255402	ENST00000530667.1	n.148C>T		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000223 AC: 3 AN: 1344836 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 660430

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: 0.00000283

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2024

The c.13G>A (p.G5S) alteration is located in exon 1 (coding exon 1) of the KCNV1 gene. This alteration results from a G to A substitution at nucleotide position 13, causing the glycine (G) at amino acid position 5 to be replaced by a serine (S). 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	0.069
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	2.3
DANN	Benign	0.88
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.49	.;T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.042	T;T
MetaSVM	Uncertain	-0.094	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.73	N;N
REVEL	Benign	0.20
Sift	Benign	1.0	T;T
Sift4G	Benign	0.93	T;T
Polyphen		0.33	B;B
Vest4		0.082
MutPred		0.22		Gain of phosphorylation at G5 (P = 0.0022);Gain of phosphorylation at G5 (P = 0.0022);
MVP		0.39
MPC		1.8
ClinPred		0.057	T
GERP RS		-0.75
Varity_R		0.043
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1324390636; hg19: chr8-110986605;