NM_000238.4:c.769A>C

Variant names:

• chr7-150958206-T-G
• rs199472875
• NM_000238.4:c.769A>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000238.4(KCNH2):​c.769A>C​(p.Asn257His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 33)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: -0.00800

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33192176).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.769A>C	p.Asn257His	missense_variant	Exon 4 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.769A>C	p.Asn257His	missense_variant	Exon 4 of 15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000532957.5	n.992A>C		non_coding_transcript_exon_variant	Exon 4 of 9	2
KCNH2	ENST00000684241.1	n.1602A>C		non_coding_transcript_exon_variant	Exon 2 of 13

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151772 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151772 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74152

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Other:1

Nov 12, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19841300, 14661677) -

-

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

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported in the following publications (PMID:14661677;PMID:19841300). -

Long QT syndrome Uncertain:1

Oct 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 257 of the KCNH2 protein (p.Asn257His). This variant is present in population databases (rs199472875, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 67526). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.46	T;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.81	T;T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	0.81	L;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.66	N;.
REVEL	Uncertain	0.55
Sift	Benign	0.54	T;.
Sift4G	Benign	0.24	T;T
Polyphen		0.036	B;.
Vest4		0.20
MutPred		0.34		Loss of stability (P = 0.1355);.;
MVP		0.92
MPC		1.3
ClinPred		0.31	T
GERP RS		3.6
Varity_R		0.11
gMVP		0.53

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: rs199472875; hg19: chr7-150655294;