rs3762452

chr1-211103486-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_172362.3(KCNH1):c.310+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,523,160 control chromosomes in the GnomAD database, including 37,378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3037 hom., cov: 33)
  • Exomes 𝑓: 0.22 (34341 hom.)
• Consequence: KCNH1 NM_172362.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.639

Genes affected

KCNH1 (HGNC:6250): (potassium voltage-gated channel subfamily H 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 channel, voltage-gated, subfamily H. This member is a pore-forming (alpha) subunit of a voltage-gated non-inactivating delayed rectifier potassium channel. It is activated at the onset of myoblast differentiation. The gene is highly expressed in brain and in myoblasts. Overexpression of the gene may confer a growth advantage to cancer cells and favor tumor cell proliferation. Alternative splicing of this gene results in two transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 1-211103486-C-T is Benign according to our data. Variant chr1-211103486-C-T is described in ClinVar as [Benign]. Clinvar id is 262807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH1	NM_172362.3	c.310+10G>A		intron_variant		ENST00000271751.10
KCNH1	NM_002238.4	c.310+10G>A		intron_variant
KCNH1	XM_047419823.1	c.310+10G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH1	ENST00000271751.10	c.310+10G>A		intron_variant		2	NM_172362.3

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29165 AN: 152056 Hom.: 3037 Cov.: 33

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.196

GnomAD3 exomes AF: 0.189 AC: 46772 AN: 247452 Hom.: 4940 AF XY: 0.193 AC XY: 25807 AN XY: 133712

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.247

Gnomad EAS exome AF: 0.120

Gnomad SAS exome AF: 0.149

Gnomad FIN exome AF: 0.230

Gnomad NFE exome AF: 0.230

Gnomad OTH exome AF: 0.202

GnomAD4 exome AF: 0.218 AC: 298787 AN: 1370986 Hom.: 34341 Cov.: 20 AF XY: 0.217 AC XY: 149011 AN XY: 686952

Gnomad4 AFR exome AF: 0.143

Gnomad4 AMR exome AF: 0.107

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.104

Gnomad4 SAS exome AF: 0.158

Gnomad4 FIN exome AF: 0.229

Gnomad4 NFE exome AF: 0.233

Gnomad4 OTH exome AF: 0.212

GnomAD4 genome AF: 0.192 AC: 29171 AN: 152174 Hom.: 3037 Cov.: 33 AF XY: 0.191 AC XY: 14229 AN XY: 74398

Gnomad4 AFR AF: 0.144

Gnomad4 AMR AF: 0.147

Gnomad4 ASJ AF: 0.251

Gnomad4 EAS AF: 0.112

Gnomad4 SAS AF: 0.150

Gnomad4 FIN AF: 0.241

Gnomad4 NFE AF: 0.230

Gnomad4 OTH AF: 0.194

Alfa AF: 0.214 Hom.: 4146

Bravo AF: 0.183

Asia WGS AF: 0.119 AC: 411 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	5.8
Dann	Benign	0.73

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: rs3762452; hg19: chr1-211276828; COSMIC: COSV55082902; COSMIC: COSV55082902;