7-150959622-G-C

Variant names:

• chr7-150959622-G-C
• NM_000238.4:c.422C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000238.4(KCNH2):​c.422C>G​(p.Pro141Arg) 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. 12/21 in silico tools predict 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. P141L) 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: 0.375

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.

• 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.2321482).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.422C>G	p.Pro141Arg	missense_variant	Exon 3 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.422C>G	p.Pro141Arg	missense_variant	Exon 3 of 15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000532957.5	n.645C>G		non_coding_transcript_exon_variant	Exon 3 of 9	2
KCNH2	ENST00000684241.1	n.1255C>G		non_coding_transcript_exon_variant	Exon 1 of 13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.056
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.23	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.014	D
Sift4G	Benign	0.53	T
Polyphen		0.18	B
Vest4		0.34
MutPred		0.27		Gain of solvent accessibility (P = 0.0411);
MVP		0.49
MPC		1.2
ClinPred		0.33	T
GERP RS		3.8
Varity_R		0.11
gMVP		0.63

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: chr7-150656710;