7-150950165-T-G

Position:

• chr7-150950165-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1 PM1 PM5 PP2

The NM_172056.3(KCNH2):​c.2401A>C​(p.Met801Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M801I) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNH2 NM_172056.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.69

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 Likely_pathogenic. Variant got 9 ACMG points.

• PS1: Transcript NM_172056.3 (KCNH2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a binding_site (size 100) in uniprot entity KCNH2_HUMAN there are 12 pathogenic changes around while only 1 benign (92%) in NM_172056.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150950163-C-A is described in Lovd as [Pathogenic].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.2398+3A>C		splice_region_variant, 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+3A>C		splice_region_variant, intron_variant		1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 5 AN: 124990 Hom.: 0 Cov.: 28 FAILED QC

Gnomad AFR AF: 0.0000298

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000266

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000339

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000130 AC: 79 AN: 609120 Hom.: 0 Cov.: 23 AF XY: 0.000120 AC XY: 39 AN XY: 325108

Gnomad4 AFR exome AF: 0.000126

Gnomad4 AMR exome AF: 0.000103

Gnomad4 ASJ exome AF: 0.000126

Gnomad4 EAS exome AF: 0.000268

Gnomad4 SAS exome AF: 0.0000142

Gnomad4 FIN exome AF: 0.000266

Gnomad4 NFE exome AF: 0.000127

Gnomad4 OTH exome AF: 0.000224

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000400 AC: 5 AN: 125042 Hom.: 0 Cov.: 28 AF XY: 0.0000497 AC XY: 3 AN XY: 60350

Gnomad4 AFR AF: 0.0000298

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000266

Gnomad4 NFE AF: 0.0000339

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.21	T
MetaSVM	Uncertain	0.13	D
REVEL	Uncertain	0.39
Sift4G	Uncertain	0.017	D
Vest4		0.30
MVP		0.26
ClinPred		0.70	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.87		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554425151; hg19: chr7-150647253;