rs199473014

Variant names:

• chr7-150947684-G-A
• rs199473014
• NM_000238.4:c.2887C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-150947684-G-A
• chr7-150947684-G-C
• chr7-150947684-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP2

The NM_000238.4(KCNH2):​c.2887C>T​(p.Pro963Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,448,824 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P963T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.76

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

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150947683-GG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 421672.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 158 curated pathogenic missense variants (we use a threshold of 10). The gene has 38 curated benign missense variants. Gene score misZ: 3.3724 (above the threshold of 3.09). Trascript score misZ: 2.4846 (below the threshold of 3.09). GenCC associations: The gene is linked to Brugada syndrome, long QT syndrome, short QT syndrome, short QT syndrome type 1, long QT syndrome 2.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.2887C>T	p.Pro963Ser	missense_variant	Exon 12 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.2887C>T	p.Pro963Ser	missense_variant	Exon 12 of 15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000330883.9	c.1867C>T	p.Pro623Ser	missense_variant	Exon 8 of 11	1		ENSP00000328531.4
KCNH2	ENST00000684241.1	n.3720C>T		non_coding_transcript_exon_variant	Exon 10 of 13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1448824 Hom.: 0 Cov.: 36 AF XY: 0.00000139 AC XY: 1 AN XY: 719732

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33294

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 43230

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25866

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39176

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 84416

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 50786

Gnomad4 NFE exome AF: 0.00000181 AC: 2 AN: 1106620

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 59798

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
CardioboostArm	Benign	0.000049
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	.;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.061
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	0.69	.;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.51
Sift	Benign	0.50	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.073	B;B
Vest4		0.41
MutPred		0.55		.;Gain of phosphorylation at P963 (P = 0.0017);
MVP		0.85
MPC		0.68
ClinPred		0.40	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.096
gMVP		0.68
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199473014; hg19: chr7-150644772;