rs146624318

Variant names:

• chr1-110517670-C-A
• rs146624318
• NM_005549.2:c.1118G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-110517670-C-A
• chr1-110517670-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005549.2(KCNA10):​c.1118G>T​(p.Arg373Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R373Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNA10 NM_005549.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.25
• Publications: 3 publications found

Genes affected

KCNA10 (HGNC:6219): (potassium voltage-gated channel subfamily A member 10) Potassium 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. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It is specifically regulated by cGMP and postulated to mediate the effects of substances that increase intracellular cGMP. This gene is intronless, and the gene is clustered with genes KCNA2 and KCNA3 on chromosome 1. [provided by RefSeq, Jul 2008]

ENSG00000301555 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005549.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA10	NM_005549.2	MANE Select	c.1118G>T	p.Arg373Leu	missense	Exon 1 of 1	NP_005540.1	Q16322

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA10	ENST00000369771.4	TSL:6 MANE Select	c.1118G>T	p.Arg373Leu	missense	Exon 1 of 1	ENSP00000358786.2	Q16322
	ENSG00000301555	ENST00000779684.1		n.87-8797C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		2.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.96	D
Vest4		0.70
MutPred		0.59		Loss of methylation at R373 (P = 0.0332)
MVP		0.94
MPC		0.21
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.85
gMVP		0.85
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs146624318; hg19: chr1-111060292; COSMIC: COSV105926318; COSMIC: COSV105926318;