rs199473546

Variant names:

• chr7-150945502-T-C
• rs199473546
• NM_000238.4:c.3343A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_000238.4(KCNH2):​c.3343A>G​(p.Met1115Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000386 in 1,553,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. M1115T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4 O:1
• Conservation: PhyloP100: 0.0270
• 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: Likely_benign. 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, short QT syndrome type 1, short QT syndrome, Brugada syndrome, long QT syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19233093).

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.3343A>G	p.Met1115Val	missense	Exon 15 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.3055A>G	p.Met1019Val	missense	Exon 13 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172057.3		c.2323A>G	p.Met775Val	missense	Exon 11 of 11	NP_742054.1	Q12809-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.3343A>G	p.Met1115Val	missense	Exon 15 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000330883.9	TSL:1	c.2323A>G	p.Met775Val	missense	Exon 11 of 11	ENSP00000328531.4	Q12809-2
	KCNH2	ENST00000713710.1		c.3277A>G	p.Met1093Val	missense	Exon 15 of 15	ENSP00000519013.1	A0AAQ5BGR0

Frequencies

GnomAD3 genomes AF: 0.0000136 AC: 2 AN: 146804 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000302

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000284 AC: 4 AN: 1407106 Hom.: 0 Cov.: 31 AF XY: 0.00000288 AC XY: 2 AN XY: 694758

African (AFR) AF: 0.00 AC: 0 AN: 31922

American (AMR) AF: 0.00 AC: 0 AN: 36650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25248

East Asian (EAS) AF: 0.00 AC: 0 AN: 36418

South Asian (SAS) AF: 0.00 AC: 0 AN: 79736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00000369 AC: 4 AN: 1083728

Other (OTH) AF: 0.00 AC: 0 AN: 58370

GnomAD4 genome AF: 0.0000136 AC: 2 AN: 146804 Hom.: 0 Cov.: 32 AF XY: 0.0000139 AC XY: 1 AN XY: 71788

African (AFR) AF: 0.00 AC: 0 AN: 39380

American (AMR) AF: 0.00 AC: 0 AN: 14924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3372

East Asian (EAS) AF: 0.00 AC: 0 AN: 4914

South Asian (SAS) AF: 0.00 AC: 0 AN: 4630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000302 AC: 2 AN: 66134

Other (OTH) AF: 0.00 AC: 0 AN: 2038

Alfa AF: 0.0000100 Hom.: 0

Bravo AF: 0.0000302

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 provided (1)
-	-	-	Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
CardioboostArm	Benign	0.000094
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	14
DANN	Benign	0.76
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	0.032	D
MutationAssessor	Benign	0.0	N
PhyloP100		0.027
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.41	N
REVEL	Uncertain	0.55
Sift	Benign	0.67	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.76		Gain of sheet (P = 0.0061)
MVP		0.98
MPC		0.17
ClinPred		0.025	T
GERP RS		1.6
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.042
gMVP		0.34
Mutation Taster		=3/97	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: rs199473546; hg19: chr7-150642590;