7-150959661-T-G

Position:

• chr7-150959661-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000238.4(KCNH2):​c.383A>C​(p.Asn128Thr) variant causes a missense change involving the alteration of a 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.47

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]

KCNH2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain PAC (size 52) in uniprot entity KCNH2_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.383A>C	p.Asn128Thr	missense_variant	3/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.383A>C	p.Asn128Thr	missense_variant	3/15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000532957.5	n.606A>C		non_coding_transcript_exon_variant	3/9	2
KCNH2	ENST00000684241.1	n.1216A>C		non_coding_transcript_exon_variant	1/13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 20, 2021

This sequence change replaces asparagine with threonine at codon 128 of the KCNH2 protein (p.Asn128Thr). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with KCNH2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D;D
Eigen	Benign	-0.12
Eigen_PC	Benign	0.064
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	0.77	N;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.9	D;.
REVEL	Uncertain	0.55
Sift	Benign	0.17	T;.
Sift4G	Benign	0.096	T;T
Polyphen		0.0080	B;.
Vest4		0.77
MutPred		0.55		Loss of sheet (P = 0.0315);.;
MVP		0.90
MPC		1.1
ClinPred		0.96	D
GERP RS		4.7
Varity_R		0.82
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-150656749;