rs1220897906

chr7-150958197-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000238.4(KCNH2):c.778G>C(p.Ala260Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000367 in 1,363,138 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A260V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000033 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.349

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3724612).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.778G>C	p.Ala260Pro	missense_variant	4/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.778G>C	p.Ala260Pro	missense_variant	4/15	1	NM_000238.4	P1
KCNH2	ENST00000532957.5	n.1001G>C		non_coding_transcript_exon_variant	4/9	2
KCNH2	ENST00000684241.1	n.1611G>C		non_coding_transcript_exon_variant	2/13

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151842 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000330 AC: 4 AN: 1211296 Hom.: 0 Cov.: 32 AF XY: 0.00000170 AC XY: 1 AN XY: 589622

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000202

Gnomad4 OTH exome AF: 0.0000404

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151842 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74180

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 06, 2024

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 260 of the KCNH2 protein (p.Ala260Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 427970). 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 tolerated. 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. -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Human Genetics, University of Leuven

Apr 30, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
CardioboostArm	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.36	T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.75	T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.57	N;.
REVEL	Uncertain	0.55
Sift	Benign	0.13	T;.
Sift4G	Benign	0.34	T;T
Polyphen		0.99	D;.
Vest4		0.16
MutPred		0.37		Gain of relative solvent accessibility (P = 0.0249);.;
MVP		0.95
MPC		1.8
ClinPred		0.52	D
GERP RS		3.6
Varity_R		0.13
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1220897906; hg19: chr7-150655285;