rs41307319

chr7-150959633-C-A

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.411G>T(p.Met137Ile) 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. 13/22 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. M137T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.974

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 23 pathogenic changes around while only 5 benign (82%) in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22006673).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.411G>T	p.Met137Ile	missense_variant	3/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.411G>T	p.Met137Ile	missense_variant	3/15	1	NM_000238.4	P1
KCNH2	ENST00000532957.5	n.634G>T		non_coding_transcript_exon_variant	3/9	2
KCNH2	ENST00000684241.1	n.1244G>T		non_coding_transcript_exon_variant	1/13

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	0.10
CardioboostArm	Benign	0.0012
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.39	T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.77	T;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	0.77	D;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.71	N;.
REVEL	Uncertain	0.35
Sift	Benign	0.40	T;.
Sift4G	Benign	0.35	T;T
Polyphen		0.0020	B;.
Vest4		0.30
MutPred		0.45		Gain of catalytic residue at M137 (P = 0.0014);.;
MVP		0.53
MPC		1.1
ClinPred		0.49	T
GERP RS		4.7
Varity_R		0.21
gMVP		0.29

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: rs41307319; hg19: chr7-150656721;