7-150949990-G-C

Position:

• chr7-150949990-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_172056.3(KCNH2):​c.2576C>G​(p.Thr859Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,401,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/13 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: KCNH2 NM_172056.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0980

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]

KCNH2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNH2. . Gene score misZ 3.3724 (greater than the threshold 3.09). Trascript score misZ 3.4405 (greater than threshold 3.09). GenCC has associacion of gene with 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=0.08544469).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.2398+178C>G		intron_variant		ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.2398+178C>G		intron_variant		1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000617 AC: 1 AN: 161984 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 86294

Gnomad AFR exome AF: 0.000118

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

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 AF: 7.13e-7 AC: 1 AN: 1401678 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 692194

Gnomad4 AFR exome AF: 0.0000316

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	1.6
DANN	Benign	0.94
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.085	T
MetaSVM	Uncertain	0.32	D
REVEL	Benign	0.25
Sift4G	Benign	0.23	T
Vest4		0.16
MVP		0.14
ClinPred		0.025	T
GERP RS		-5.1

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: rs41314366; hg19: chr7-150647078;