7-150957394-T-G

Position:

• chr7-150957394-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000238.4(KCNH2):​c.1025A>C​(p.Asp342Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. D342V) 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: 7.97

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 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.1025A>C	p.Asp342Ala	missense_variant	5/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.1025A>C	p.Asp342Ala	missense_variant	5/15	1	NM_000238.4	P1
KCNH2	ENST00000532957.5	n.1248A>C		non_coding_transcript_exon_variant	5/9	2
KCNH2	ENST00000684241.1	n.1858A>C		non_coding_transcript_exon_variant	3/13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250706 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135754

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.70	T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.0	D;.
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0040	D;.
Sift4G	Benign	0.088	T;T
Polyphen		0.97	D;.
Vest4		0.51
MutPred		0.51		Loss of loop (P = 0.0128);.;
MVP		0.93
MPC		2.4
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.37
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199472889; hg19: chr7-150654482;