17-63524310-C-A

Variant names:

• chr17-63524310-C-A
• NM_001278919.2:c.248C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001278919.2(KCNH6):​c.248C>A​(p.Ala83Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNH6 NM_001278919.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.30
• Publications: 0 publications found

Genes affected

KCNH6 (HGNC:18862): (potassium voltage-gated channel subfamily H member 6) 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 channel, voltage-gated, subfamily H. This member is a pore-forming (alpha) subunit. Alternative splicing results in multiple transcript variants that encode different isoforms. [provided by RefSeq, Jul 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278919.2. 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
	KCNH6	NM_001278919.2	MANE Select	c.248C>A	p.Ala83Glu	missense	Exon 2 of 13	NP_001265848.1	Q9H252-4
	KCNH6	NM_030779.4		c.248C>A	p.Ala83Glu	missense	Exon 2 of 14	NP_110406.1	Q9H252-1
	KCNH6	NM_173092.4		c.248C>A	p.Ala83Glu	missense	Exon 2 of 15	NP_775115.1	Q9H252-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH6	ENST00000314672.10	TSL:2 MANE Select	c.248C>A	p.Ala83Glu	missense	Exon 2 of 13	ENSP00000318212.5	Q9H252-4
	KCNH6	ENST00000583023.1	TSL:1	c.248C>A	p.Ala83Glu	missense	Exon 2 of 14	ENSP00000463533.1	Q9H252-1
	KCNH6	ENST00000580652.5	TSL:1	c.248C>A	p.Ala83Glu	missense	Exon 2 of 6	ENSP00000464672.1	Q9H252-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Benign	0.90
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.3	L
PhyloP100		3.3
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.68
Sift	Benign	0.73	T
Sift4G	Benign	0.87	T
Polyphen		0.93	P
Vest4		0.48
MutPred		0.62		Gain of disorder (P = 0.0363)
MVP		0.76
MPC		0.25
ClinPred		0.74	D
GERP RS		5.3
Varity_R		0.53
gMVP		0.32

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

Other links and lift over

hg19: chr17-61601671; COSMIC: COSV59008910; COSMIC: COSV59008910;