rs747437736

Variant names:

• chr7-150957436-C-T
• rs747437736
• NM_000238.4:c.983G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP2 PP3 BS2_Supporting

The NM_000238.4(KCNH2):​c.983G>A​(p.Arg328His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,614,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R328C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 7.86
• Publications: 2 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: Uncertain_significance. The variant received 1 ACMG points.

• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.748
• BS2: High AC in GnomAdExome4 at 8 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.983G>A	p.Arg328His	missense	Exon 5 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.695G>A	p.Arg232His	missense	Exon 3 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172056.3		c.983G>A	p.Arg328His	missense	Exon 5 of 9	NP_742053.1	Q12809-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.983G>A	p.Arg328His	missense	Exon 5 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000713710.1		c.983G>A	p.Arg328His	missense	Exon 5 of 15	ENSP00000519013.1	A0AAQ5BGR0
	KCNH2	ENST00000713701.1		c.683G>A	p.Arg228His	missense	Exon 4 of 14	ENSP00000519004.1	A0AAQ5BGQ9

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 250798 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461808 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727222

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111956

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74382

African (AFR) AF: 0.0000723 AC: 3 AN: 41476

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68056

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Long QT syndrome (2)
-	2	-	not provided (2)
-	1	-	Cardiac arrhythmia (1)
-	1	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
CardioboostArm	Benign	0.088
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.019	D
Sift4G	Benign	0.34	T
Polyphen		0.57	P
Vest4		0.76
MutPred		0.51		Gain of ubiquitination at K332 (P = 0.0398)
MVP		0.94
MPC		2.3
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.20
gMVP		0.72
Mutation Taster		=43/57	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: rs747437736; hg19: chr7-150654524; COSMIC: COSV51223496;