7-150974783-C-T

Variant names:

• chr7-150974783-C-T
• rs794728494
• NM_000238.4:c.235G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM1 PP2 BS2

The NM_000238.4(KCNH2):​c.235G>A​(p.Ala79Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000757 in 1,452,944 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A79S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.146
• Publications: 1 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), G2P, Ambry Genetics
• short QT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 24 uncertain in NM_000238.4
• 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, short QT syndrome type 1, short QT syndrome, Brugada syndrome, long QT syndrome.
• BS2: High AC in GnomAdExome4 at 11 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	NM_000238.4	MANE Select	c.235G>A	p.Ala79Thr	missense	Exon 2 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_172056.3		c.235G>A	p.Ala79Thr	missense	Exon 2 of 9	NP_742053.1	Q12809-5
	KCNH2	NM_001406755.1		c.58G>A	p.Ala20Thr	missense	Exon 2 of 9	NP_001393684.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.235G>A	p.Ala79Thr	missense	Exon 2 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000713710.1		c.235G>A	p.Ala79Thr	missense	Exon 2 of 15	ENSP00000519013.1	A0AAQ5BGR0
	KCNH2	ENST00000945647.1		c.235G>A	p.Ala79Thr	missense	Exon 2 of 14	ENSP00000615706.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000437 AC: 1 AN: 228884 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000299

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000757 AC: 11 AN: 1452944 Hom.: 0 Cov.: 34 AF XY: 0.0000125 AC XY: 9 AN XY: 722236

African (AFR) AF: 0.00 AC: 0 AN: 33206

American (AMR) AF: 0.0000227 AC: 1 AN: 44120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25896

East Asian (EAS) AF: 0.00 AC: 0 AN: 39318

South Asian (SAS) AF: 0.00 AC: 0 AN: 85414

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51912

Middle Eastern (MID) AF: 0.000198 AC: 1 AN: 5054

European-Non Finnish (NFE) AF: 0.00000722 AC: 8 AN: 1108214

Other (OTH) AF: 0.0000167 AC: 1 AN: 59810

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Long QT syndrome (2)
-	1	-	Cardiac arrhythmia (1)
-	1	-	not specified (1)
-	1	-	Short QT syndrome type 1;C3150943:Long QT syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
CardioboostArm	Benign	0.00057
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Benign	0.36	N
PhyloP100		0.15
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.43	N
REVEL	Uncertain	0.48
Sift	Uncertain	0.019	D
Sift4G	Benign	0.090	T
Polyphen		0.0	B
Vest4		0.56
MutPred		0.43		Gain of phosphorylation at A79 (P = 0.035)
MVP		0.55
MPC		1.1
ClinPred		0.52	D
GERP RS		4.4
Varity_R		0.24
gMVP		0.88
Mutation Taster		=39/61	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs794728494; hg19: chr7-150671871;