rs772977598

Positions:

• chr7-150947710-C-A
• chr7-150947710-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000238.4(KCNH2):​c.2861G>T​(p.Arg954Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,432,902 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R954C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0620

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_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 3 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150947711-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.2861G>T	p.Arg954Leu	missense_variant	12/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.2861G>T	p.Arg954Leu	missense_variant	12/15	1	NM_000238.4	P1
KCNH2	ENST00000330883.9	c.1841G>T	p.Arg614Leu	missense_variant	8/11	1
KCNH2	ENST00000684241.1	n.3694G>T		non_coding_transcript_exon_variant	10/13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1432902 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 710744

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: 9.09e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	.;T
Eigen	Benign	0.14
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	0.69	.;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.8	N;N
REVEL	Pathogenic	0.65
Sift	Benign	0.13	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.90	P;P
Vest4		0.54
MutPred		0.52		.;Gain of sheet (P = 0.0827);
MVP		0.93
MPC		0.31
ClinPred		0.45	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.2
Varity_R		0.22
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs772977598; hg19: chr7-150644798; COSMIC: COSV100060264; COSMIC: COSV100060264;