rs78247304

Variant names:

• chr2-162446391-C-T
• rs78247304
• NM_033272.4:c.1181G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP3 BP4_Moderate BS2

The NM_033272.4(KCNH7):​c.1181G>A​(p.Arg394His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,613,456 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R394C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00059 (2 hom., cov: 32)
  • Exomes 𝑓: 0.000091 (1 hom.)
• Consequence: KCNH7 NM_033272.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.91
• Publications: 9 publications found

Genes affected

KCNH7 (HGNC:18863): (potassium voltage-gated channel subfamily H member 7) 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. There are at least two alternatively spliced transcript variants derived from this gene and encoding distinct isoforms. [provided by RefSeq, Jul 2008]

KCNH7 Gene-Disease associations (from GenCC):

• epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, phyloP100way_vertebrate, REVEL, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.14764172).
• BS2: High AC in GnomAd4 at 90 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033272.4. 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
	KCNH7	NM_033272.4	MANE Select	c.1181G>A	p.Arg394His	missense	Exon 7 of 16	NP_150375.2
	KCNH7	NM_173162.3		c.1160G>A	p.Arg387His	missense	Exon 6 of 8	NP_775185.1	Q9NS40-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH7	ENST00000332142.10	TSL:1 MANE Select	c.1181G>A	p.Arg394His	missense	Exon 7 of 16	ENSP00000331727.5	Q9NS40-1
	KCNH7	ENST00000328032.8	TSL:1	c.1160G>A	p.Arg387His	missense	Exon 6 of 8	ENSP00000333781.4	Q9NS40-2

Frequencies

GnomAD3 genomes AF: 0.000592 AC: 90 AN: 152086 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000760 AC: 19 AN: 249994 AF XY: 0.0000815

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000910 AC: 133 AN: 1461254 Hom.: 1 Cov.: 32 AF XY: 0.0000894 AC XY: 65 AN XY: 726882

African (AFR) AF: 0.0000299 AC: 1 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39680

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86202

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.000107 AC: 119 AN: 1111626

Other (OTH) AF: 0.0000331 AC: 2 AN: 60360

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152202 Hom.: 2 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74412

African (AFR) AF: 0.0000482 AC: 2 AN: 41528

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000144 Hom.: 0

Bravo AF: 0.000774

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.000218

EpiControl AF: 0.000297

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.41	T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.15	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.55
MVP		0.93
MPC		2.3
ClinPred		0.85	D
GERP RS		5.5
Varity_R		0.39
gMVP		0.79
Mutation Taster		=24/76	disease causing

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: rs78247304; hg19: chr2-163302901; COSMIC: COSV59811906;