rs199473548

Variant names:

• chr7-150945385-C-A
• rs199473548
• NM_000238.4:c.3460G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-150945385-C-A
• chr7-150945385-C-G
• chr7-150945385-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000238.4(KCNH2):​c.3460G>T​(p.Gly1154Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,438,524 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. G1154S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.424
• 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), 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 2 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=0.32365382).

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.3460G>T	p.Gly1154Cys	missense	Exon 15 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.3172G>T	p.Gly1058Cys	missense	Exon 13 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172057.3		c.2440G>T	p.Gly814Cys	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.3460G>T	p.Gly1154Cys	missense	Exon 15 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000330883.9	TSL:1	c.2440G>T	p.Gly814Cys	missense	Exon 11 of 11	ENSP00000328531.4	Q12809-2
	KCNH2	ENST00000713710.1		c.3394G>T	p.Gly1132Cys	missense	Exon 15 of 15	ENSP00000519013.1	A0AAQ5BGR0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1438524 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 713324

African (AFR) AF: 0.00 AC: 0 AN: 33064

American (AMR) AF: 0.00 AC: 0 AN: 41978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25652

East Asian (EAS) AF: 0.00 AC: 0 AN: 38580

South Asian (SAS) AF: 0.00 AC: 0 AN: 82616

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50652

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5298

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1101284

Other (OTH) AF: 0.00 AC: 0 AN: 59400

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
CardioboostArm	Uncertain	0.22
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.32	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.1	L
PhyloP100		0.42
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.55
Sift	Benign	0.092	T
Sift4G	Benign	0.19	T
Polyphen		1.0	D
Vest4		0.21
MutPred		0.18		Loss of relative solvent accessibility (P = 0.0071)
MVP		0.87
MPC		0.22
ClinPred		0.54	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.45
Mutation Taster		=45/55	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: rs199473548; hg19: chr7-150642473;