7-150945409-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000238.4(KCNH2):c.3436A>G(p.Thr1146Ala) 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 benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1146S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.14

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10389626).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.3436A>G	p.Thr1146Ala	missense_variant	15/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.3436A>G	p.Thr1146Ala	missense_variant	15/15	1	NM_000238.4	P1
KCNH2	ENST00000330883.9	c.2416A>G	p.Thr806Ala	missense_variant	11/11	1
KCNH2	ENST00000684241.1	n.4269A>G		non_coding_transcript_exon_variant	13/13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000519 AC: 1 AN: 192848 Hom.: 0 AF XY: 0.00000958 AC XY: 1 AN XY: 104412

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
CardioboostArm	Benign	4.2e-7
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	20
Dann	Uncertain	0.99
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.75	T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.10	T;T
MetaSVM	Uncertain	0.41	D
MutationTaster	Benign	0.60	D;N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.71	N;N
REVEL	Uncertain	0.45
Sift	Benign	0.78	T;T
Sift4G	Benign	0.76	T;T
Polyphen		0.020	B;B
Vest4		0.29
MutPred		0.12		.;Loss of phosphorylation at T1146 (P = 0.0409);
MVP		0.83
MPC		0.27
ClinPred		0.068	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.059
gMVP		0.33

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: rs778879572; hg19: chr7-150642497;