rs199473498

chr7-150959718-A-Cchr7-150959718-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 8P and 2B. PM1 PM2 PP3_Strong BP6_Moderate

The NM_000238.4(KCNH2):c.326T>G(p.Leu109Arg) 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 Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L109Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 3.46

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 4 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• BP6: Variant 7-150959718-A-C is Benign according to our data. Variant chr7-150959718-A-C is described in ClinVar as [Benign]. Clinvar id is 67484.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.326T>G	p.Leu109Arg	missense_variant	3/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.326T>G	p.Leu109Arg	missense_variant	3/15	1	NM_000238.4	P1
KCNH2	ENST00000532957.5	n.549T>G		non_coding_transcript_exon_variant	3/9	2
KCNH2	ENST00000684241.1	n.1159T>G		non_coding_transcript_exon_variant	1/13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

not provided Other:1

not provided, no classification provided

literature only

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
CardioboostArm	Benign	0.0036
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Pathogenic	27
Dann	Benign	0.96
DEOGEN2	Pathogenic	0.80	D;D
Eigen	Benign	-0.14
Eigen_PC	Benign	0.026
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.80	T;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	0.94	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.5	N;.
REVEL	Pathogenic	0.71
Sift	Benign	0.63	T;.
Sift4G	Benign	0.60	T;D
Polyphen		0.0010	B;.
Vest4		0.75
MutPred		0.92		Loss of sheet (P = 0.0817);.;
MVP		1.0
MPC		1.4
ClinPred		0.59	D
GERP RS		4.8
Varity_R		0.75
gMVP		0.98

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: rs199473498; hg19: chr7-150656806;