7-150947833-G-T

Variant names:

• chr7-150947833-G-T
• rs77331749
• NM_000238.4:c.2738C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_000238.4(KCNH2):​c.2738C>A​(p.Ala913Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000292 in 1,372,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A913V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.134
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• short QT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• short QT syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 long QT syndrome 2, Brugada syndrome, short QT syndrome type 1, short QT syndrome, long QT syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.054291397).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000238.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	NM_000238.4	MANE Select	c.2738C>A	p.Ala913Glu	missense	Exon 12 of 15	NP_000229.1
	KCNH2	NM_001406753.1		c.2450C>A	p.Ala817Glu	missense	Exon 10 of 13	NP_001393682.1
	KCNH2	NM_172057.3		c.1718C>A	p.Ala573Glu	missense	Exon 8 of 11	NP_742054.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.2738C>A	p.Ala913Glu	missense	Exon 12 of 15	ENSP00000262186.5
	KCNH2	ENST00000330883.9	TSL:1	c.1718C>A	p.Ala573Glu	missense	Exon 8 of 11	ENSP00000328531.4
	KCNH2	ENST00000713710.1		c.2672C>A	p.Ala891Glu	missense	Exon 12 of 15	ENSP00000519013.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000292 AC: 4 AN: 1372088 Hom.: 0 Cov.: 36 AF XY: 0.00000444 AC XY: 3 AN XY: 676160

African (AFR) AF: 0.00 AC: 0 AN: 31208

American (AMR) AF: 0.00 AC: 0 AN: 34088

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24282

East Asian (EAS) AF: 0.00 AC: 0 AN: 35556

South Asian (SAS) AF: 0.00 AC: 0 AN: 77286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4042

European-Non Finnish (NFE) AF: 0.00000373 AC: 4 AN: 1073722

Other (OTH) AF: 0.00 AC: 0 AN: 57204

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Dec 04, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Long QT syndrome Uncertain:1

May 09, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
CardioboostArm	Benign	0.0000038
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.60	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.054	T
MetaSVM	Uncertain	-0.093	T
MutationAssessor	Benign	-0.69	N
PhyloP100		0.13
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.22	N
REVEL	Uncertain	0.48
Sift	Benign	0.85	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.23
MutPred		0.30		Gain of solvent accessibility (P = 0.0456)
MVP		0.62
MPC		0.20
ClinPred		0.037	T
GERP RS		0.11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.056
gMVP		0.60
Mutation Taster		=86/14	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

Other links and lift over

dbSNP: rs77331749; hg19: chr7-150644921;