rs863225288

Positions:

• chr7-150951607-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000238.4(KCNH2):​c.1786C>G​(p.Pro596Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P596L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.13

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a topological_domain Extracellular (size 42) in uniprot entity KCNH2_HUMAN there are 29 pathogenic changes around while only 0 benign (100%) 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 chr7-150951606-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843
• PP5: Variant 7-150951607-G-C is Pathogenic according to our data. Variant chr7-150951607-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 218093.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.1786C>G	p.Pro596Ala	missense_variant	7/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.1786C>G	p.Pro596Ala	missense_variant	7/15	1	NM_000238.4	ENSP00000262186	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

case-control

Center of Genomic medicine, Geneva, University Hospital of Geneva

Nov 04, 2015

This variant (Pro596Ala) is also present in the father who has the same pathology (long QT syndrome). This missense variant has never been reported before. However, other variants affecting the same amino acid (proline 596) have been reported by ClinVar as pathogenic: Pro596Arg and Pro596His. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Benign	0.58
DEOGEN2	Pathogenic	0.88	.;D;D
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.3	.;M;.
MutationTaster	Benign	0.59	D;N;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.0	D;D;.
REVEL	Pathogenic	0.70
Sift	Benign	0.17	T;T;.
Sift4G	Benign	0.16	T;T;T
Polyphen		0.20	B;B;.
Vest4		0.60
MutPred		0.78		.;Loss of loop (P = 0.0804);.;
MVP		0.95
MPC		1.6
ClinPred		0.75	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs863225288; hg19: chr7-150648695;