rs139247073

Variant names:

• chr7-150950012-C-G
• rs139247073
• NM_000238.4:c.2398+156G>C

Your query was ambiguous. Multiple possible variants found:

• chr7-150950012-C-G
• chr7-150950012-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2 BP4_Strong BS2_Supporting

The NM_172056.3(KCNH2):​c.2554G>C​(p.Gly852Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000493 in 1,418,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/15 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: KCNH2 NM_172056.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01

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: Likely_benign. The variant received -4 ACMG points.

• PP2: Missense variant in the KCNH2 gene, where missense mutations are typically associated with disease (based on misZ statistic). 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: 3.4405 (above 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.06773761).
• BS2: High AC in GnomAdExome4 at 7 AD,Digenic gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.2398+156G>C		intron_variant	Intron 9 of 14	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.2398+156G>C		intron_variant	Intron 9 of 14	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000493 AC: 7 AN: 1418644 Hom.: 0 Cov.: 31 AF XY: 0.00000285 AC XY: 2 AN XY: 702526

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 32074

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 37738

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25478

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 36394

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 81122

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 50714

Gnomad4 NFE exome AF: 0.00000642 AC: 7 AN: 1090630

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 58782

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	2.1
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.068	T
MetaSVM	Uncertain	0.30	D
REVEL	Benign	0.26
Sift4G	Uncertain	0.013	D
Vest4		0.086
MVP		0.068
ClinPred		0.056	T
GERP RS		-4.8
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs139247073; hg19: chr7-150647100;