rs41307270

chr7-150947043-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000238.4(KCNH2):c.3164G>A(p.Arg1055Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000246 in 1,584,746 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1055G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000048 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3 O:1
• Conservation: PhyloP100: 2.45

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.038001984).
• BP6: Variant 7-150947043-C-T is Benign according to our data. Variant chr7-150947043-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67475.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2, not_provided=1, Likely_benign=2}. Variant chr7-150947043-C-T is described in Lovd as [Benign]. Variant chr7-150947043-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 7 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.3164G>A	p.Arg1055Gln	missense_variant	14/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.3164G>A	p.Arg1055Gln	missense_variant	14/15	1	NM_000238.4	P1
KCNH2	ENST00000330883.9	c.2144G>A	p.Arg715Gln	missense_variant	10/11	1
KCNH2	ENST00000684241.1	n.3997G>A		non_coding_transcript_exon_variant	12/13

Frequencies

GnomAD3 genomes AF: 0.0000476 AC: 7 AN: 147096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00103

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000298

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000901 AC: 22 AN: 244180 Hom.: 0 AF XY: 0.000106 AC XY: 14 AN XY: 132050

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000987

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000273

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000223 AC: 32 AN: 1437532 Hom.: 0 Cov.: 33 AF XY: 0.0000281 AC XY: 20 AN XY: 712652

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000230

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000309

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000164

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000475 AC: 7 AN: 147214 Hom.: 0 Cov.: 32 AF XY: 0.0000559 AC XY: 4 AN XY: 71498

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00104

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000298

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000638 Hom.: 0

Bravo AF: 0.0000831

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

Cardiac arrhythmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 01, 2019

Variant of Uncertain Significance due to insufficient evidence: This missense variant replaces arginine with glutamine at codon 1055 of the KCNH2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 24/275338 chromosomes (20/19794 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 12, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 15, 2023

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

-

This variant has been reported in the following publications (PMID:16487223). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
CardioboostArm	Benign	0.000078
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Uncertain	0.010
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.038	T;T
MetaSVM	Benign	-0.42	T
MutationTaster	Benign	0.56	N;N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.43
Sift	Benign	0.56	T;T
Sift4G	Benign	0.57	T;T
Polyphen		0.086	B;B
Vest4		0.47
MVP		0.94
MPC		0.67
ClinPred		0.090	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.57

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: rs41307270; hg19: chr7-150644131;