2-162384777-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BA1

The NM_033272.4(KCNH7):c.2873G>C(p.Gly958Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,612,714 control chromosomes in the GnomAD database, including 1,803 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.062 (932 hom., cov: 32)
  • Exomes 𝑓: 0.0079 (871 hom.)
• Consequence: KCNH7 NM_033272.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.11

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KCNH7
• BP4: Computational evidence support a benign effect (MetaRNN=0.0014646053).
• BP6: Variant 2-162384777-C-G is Benign according to our data. Variant chr2-162384777-C-G is described in ClinVar as [Benign]. Clinvar id is 3057010.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH7	NM_033272.4	c.2873G>C	p.Gly958Ala	missense_variant	13/16	ENST00000332142.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH7	ENST00000332142.10	c.2873G>C	p.Gly958Ala	missense_variant	13/16	1	NM_033272.4	P1

Frequencies

GnomAD3 genomes AF: 0.0620 AC: 9412 AN: 151744 Hom.: 929 Cov.: 32

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.0482

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.0512

GnomAD3 exomes AF: 0.0188 AC: 4706 AN: 250650 Hom.: 384 AF XY: 0.0144 AC XY: 1954 AN XY: 135452

Gnomad AFR exome AF: 0.211

Gnomad AMR exome AF: 0.0127

Gnomad ASJ exome AF: 0.0543

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00174

Gnomad OTH exome AF: 0.0144

GnomAD4 exome AF: 0.00792 AC: 11568 AN: 1460852 Hom.: 871 Cov.: 31 AF XY: 0.00707 AC XY: 5140 AN XY: 726750

Gnomad4 AFR exome AF: 0.215

Gnomad4 AMR exome AF: 0.0146

Gnomad4 ASJ exome AF: 0.0556

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000452

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000885

Gnomad4 OTH exome AF: 0.0192

GnomAD4 genome AF: 0.0621 AC: 9430 AN: 151862 Hom.: 932 Cov.: 32 AF XY: 0.0600 AC XY: 4453 AN XY: 74214

Gnomad4 AFR AF: 0.208

Gnomad4 AMR AF: 0.0267

Gnomad4 ASJ AF: 0.0482

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00150

Gnomad4 OTH AF: 0.0507

Alfa AF: 0.00915 Hom.: 16

Bravo AF: 0.0704

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.202 AC: 891

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.0225 AC: 2734

Asia WGS AF: 0.0120 AC: 41 AN: 3478

EpiCase AF: 0.00311

EpiControl AF: 0.00225

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

KCNH7-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	16
Dann	Benign	0.48
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.81	T;T
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-0.77	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.25	T
Sift4G	Benign	0.78	T;T
Polyphen		0.0020	.;B
Vest4		0.058
MPC		0.10
ClinPred		0.0032	T
GERP RS		3.8
Varity_R		0.035
gMVP		0.19

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: rs6757850; hg19: chr2-163241287;