rs199472825

Variant names:

• chr7-150977867-T-C
• NM_000238.4:c.47A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-150977867-T-C
• chr7-150977867-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000238.4(KCNH2):​c.47A>G​(p.Asp16Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 27)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.51

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.47A>G	p.Asp16Gly	missense_variant	Exon 1 of 15	ENST00000262186.10	NP_000229.1
KCNH2	NM_172056.3	c.47A>G	p.Asp16Gly	missense_variant	Exon 1 of 9		NP_742053.1
KCNH2	NR_176254.1	n.455A>G		non_coding_transcript_exon_variant	Exon 1 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.47A>G	p.Asp16Gly	missense_variant	Exon 1 of 15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000532957.5	n.270A>G		non_coding_transcript_exon_variant	Exon 1 of 9	2

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 27

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Uncertain:2

Jun 09, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with glycine at codon 16 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with KCNH2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

May 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 16 of the KCNH2 protein (p.Asp16Gly). This missense change has been observed in individual(s) with clinical features of KCNH2-related conditions (Invitae). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Cardiovascular phenotype Uncertain:1

Apr 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D16G variant (also known as c.47A>G), located in coding exon 1 of the KCNH2 gene, results from an A to G substitution at nucleotide position 47. The aspartic acid at codon 16 is replaced by glycine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.059
Eigen_PC	Benign	-0.019
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Benign	1.5	L
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.55
Sift	Benign	0.49	T
Sift4G	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.36
MutPred		0.78		Loss of ubiquitination at K21 (P = 0.0526);
MVP		0.84
MPC		1.3
ClinPred		0.74	D
GERP RS		2.1
Varity_R		0.35
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-150674955;