rs41314366

chr7-150949990-G-Achr7-150949990-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000238.4(KCNH2):c.2398+178C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000171 in 1,553,936 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00081 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: KCNH2 NM_000238.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0980

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005583346).
• BP6: Variant 7-150949990-G-A is Benign according to our data. Variant chr7-150949990-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 191542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 117 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.2398+178C>T		intron_variant		ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.2398+178C>T		intron_variant		1	NM_000238.4	P1

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152140 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000173 AC: 28 AN: 161984 Hom.: 0 AF XY: 0.000162 AC XY: 14 AN XY: 86294

Gnomad AFR exome AF: 0.00295

Gnomad AMR exome AF: 0.0000399

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000887

Gnomad SAS exome AF: 0.0000420

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000101 AC: 142 AN: 1401678 Hom.: 0 Cov.: 31 AF XY: 0.0000997 AC XY: 69 AN XY: 692194

Gnomad4 AFR exome AF: 0.00256

Gnomad4 AMR exome AF: 0.0000556

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000444

Gnomad4 OTH exome AF: 0.0000517

GnomAD4 genome AF: 0.000814 AC: 124 AN: 152258 Hom.: 1 Cov.: 31 AF XY: 0.000819 AC XY: 61 AN XY: 74446

Gnomad4 AFR AF: 0.00274

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000227 Hom.: 0

Bravo AF: 0.000899

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00130 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000714 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The KCNH2 p.Thr859Met variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs41314366) and ClinVar (classified as benign by Color and likely benign by Biesecker Lab/Clinical Genomics Section, National Institutes of Health). The variant was identified in control databases in 54 of 193350 chromosomes at a frequency of 0.0002793 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 51 of 17166 chromosomes (freq: 0.002971), East Asian in 1 of 12840 chromosomes (freq: 0.000078), South Asian in 1 of 23808 chromosomes (freq: 0.000042) and Latino in 1 of 25940 chromosomes (freq: 0.000039), but was not observed in the Ashkenazi Jewish, European (Finnish), European (non-Finnish), and Other populations. The p.Thr859 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Cardiac arrhythmia Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 16, 2018

- -

KCNH2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 10, 2021

This variant is classified as likely 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
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	1.3
Dann	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0056	T
MetaSVM	Uncertain	0.25	D
MutationTaster	Benign	1.0	N;N;N;N
REVEL	Benign	0.26
Sift4G	Benign	0.24	T
Vest4		0.15
MVP		0.082
ClinPred		0.016	T
GERP RS		-5.1

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: rs41314366; hg19: chr7-150647078; COSMIC: COSV100060755;