chr7-150947428-G-C

Variant names:

• chr7-150947428-G-C
• rs41313764
• NM_000238.4:c.3052C>G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_000238.4(KCNH2):​c.3052C>G​(p.Pro1018Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000386 in 1,556,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 1.46

Genes affected

KCNH2 (HGNC:6251): (potassium voltage-gated channel subfamily H member 2) This gene encodes a component of a voltage-activated potassium channel found in cardiac muscle, nerve cells, and microglia. Four copies of this protein interact with one copy of the KCNE2 protein to form a functional potassium channel. Mutations in this gene can cause long QT syndrome type 2 (LQT2). Transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2766472).
• BS2: High AC in GnomAdExome4 at 56 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.3052C>G	p.Pro1018Ala	missense_variant	Exon 13 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.3052C>G	p.Pro1018Ala	missense_variant	Exon 13 of 15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000330883.9	c.2032C>G	p.Pro678Ala	missense_variant	Exon 9 of 11	1		ENSP00000328531.4
KCNH2	ENST00000684241.1	n.3885C>G		non_coding_transcript_exon_variant	Exon 11 of 13

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152124 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000256 AC: 4 AN: 156200 Hom.: 0 AF XY: 0.0000355 AC XY: 3 AN XY: 84544

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000402

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000495

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000399 AC: 56 AN: 1404134 Hom.: 0 Cov.: 36 AF XY: 0.0000375 AC XY: 26 AN XY: 693004

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000277

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000490

Gnomad4 OTH exome AF: 0.0000343

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74456

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000908 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Jan 12, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KCNH2 c.3052C>G; p.Pro1018Ala variant (rs41313764) is reported in the literature in an individual affected with atrial fibrillation, though it was not demonstrated to be disease-causing (Donate Puertas 2018). This variant is found on only four chromosomes (4/156200 alleles) in the Genome Aggregation Database. The proline at codon 1018 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Pro1018Ala variant is uncertain at this time. References: Donate Puertas R et al. Atrial Structural Remodeling Gene Variants in Patients with Atrial Fibrillation. Biomed Res Int. 2018;2018:4862480. -

May 27, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in individuals with various cardiac disorders, including dilated cardiomyopathy, ventricular tachycardia, paroxysmal atrial fibrillation, and unspecified arrhythmia (Doate Puertas et al., 2018; Herkert et al., 2018; van Lint et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29517769, 30847666, 30276209) -

Long QT syndrome Uncertain:2

Nov 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1018 of the KCNH2 protein (p.Pro1018Ala). This variant is present in population databases (rs41313764, gnomAD 0.005%). This missense change has been observed in individual(s) with atrial fibrillation, unknown arrhythmia, left ventricular noncompaction and dilated cardiomyopathy (PMID: 28798025, 29517769, 30276209, 30847666). ClinVar contains an entry for this variant (Variation ID: 200520). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Nov 30, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with alanine at codon 1018 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with arrhythmias (PMID: 30276209, 30847666). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 29517769) and in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 28798025). This variant has been identified in 4/156200 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiac arrhythmia Uncertain:1

Dec 19, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with alanine at codon 1018 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with arrhythmias (PMID: 30276209, 30847666). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 29517769) and in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 28798025). This variant has been identified in 4/156200 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.35	.;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.78	T;T
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	1.4	.;L
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.56
Sift	Benign	0.24	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.0060	B;B
Vest4		0.25
MutPred		0.27		.;Loss of glycosylation at P1018 (P = 0.02);
MVP		0.85
MPC		0.65
ClinPred		0.094	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.4
Varity_R		0.086
gMVP		0.54

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: rs41313764; hg19: chr7-150644516; COSMIC: COSV105086779; COSMIC: COSV105086779;