rs104894021

Positions:

• chr7-150951629-G-C
• chr7-150951629-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1 PM1 PM2 PM5 PP3_Strong PP5

The NM_000238.4(KCNH2):​c.1764C>G​(p.Asn588Lys) 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 (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N588D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 0.270

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 15 ACMG points.

• PS1: Transcript NM_000238.4 (KCNH2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 14437
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 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 chr7-150951631-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67266.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 7-150951629-G-C is Pathogenic according to our data. Variant chr7-150951629-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 14436.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.1764C>G	p.Asn588Lys	missense_variant	7/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.1764C>G	p.Asn588Lys	missense_variant	7/15	1	NM_000238.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Short QT syndrome type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2005

- -

Short QT syndrome Other:1

not provided, no classification provided

literature only

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

-

This variant has been reported as associated with Short QT syndrome in the following publications (PMID:14676148;PMID:15828882;PMID:19088443;PMID:19439805;PMID:19501051;PMID:22194679). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	.;D;D
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Benign	0.65	.;N;.
MutationTaster	Benign	0.86	D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-4.0	D;D;.
REVEL	Uncertain	0.60
Sift	Benign	0.59	T;T;.
Sift4G	Benign	0.78	T;T;T
Polyphen		0.014	B;B;.
Vest4		0.82
MutPred		0.89		.;Gain of ubiquitination at N588 (P = 0.0325);.;
MVP		0.91
MPC		2.0
ClinPred		0.75	D
GERP RS		4.3
Varity_R		0.45
gMVP		0.91

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: rs104894021; hg19: chr7-150648717;