rs199473549

Variant names:

• chr7-150958094-C-A
• rs199473549
• NM_000238.4:c.881G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-150958094-C-A
• chr7-150958094-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000238.4(KCNH2):​c.881G>T​(p.Gly294Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000176 in 1,135,536 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. G294A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 0.442
• Publications: 5 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: Uncertain_significance. The variant received 3 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.

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.881G>T	p.Gly294Val	missense	Exon 4 of 15	NP_000229.1
	KCNH2	NM_001406753.1		c.593G>T	p.Gly198Val	missense	Exon 2 of 13	NP_001393682.1
	KCNH2	NM_172056.3		c.881G>T	p.Gly294Val	missense	Exon 4 of 9	NP_742053.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.881G>T	p.Gly294Val	missense	Exon 4 of 15	ENSP00000262186.5
	KCNH2	ENST00000713710.1		c.881G>T	p.Gly294Val	missense	Exon 4 of 15	ENSP00000519013.1
	KCNH2	ENST00000713701.1		c.581G>T	p.Gly194Val	missense	Exon 3 of 14	ENSP00000519004.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000176 AC: 2 AN: 1135536 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 542114

African (AFR) AF: 0.00 AC: 0 AN: 22968

American (AMR) AF: 0.00 AC: 0 AN: 8886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15172

East Asian (EAS) AF: 0.00 AC: 0 AN: 26464

South Asian (SAS) AF: 0.00 AC: 0 AN: 33570

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25116

Middle Eastern (MID) AF: 0.000324 AC: 1 AN: 3086

European-Non Finnish (NFE) AF: 0.00000105 AC: 1 AN: 953882

Other (OTH) AF: 0.00 AC: 0 AN: 46392

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Long QT syndrome (1)
-	1	-	Short QT syndrome type 1;C3150943:Long QT syndrome 2 (1)
-	-	-	SUDDEN INFANT DEATH SYNDROME (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
CardioboostArm	Benign	0.025
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	0.0	N
PhyloP100		0.44
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.64
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.20	T
Polyphen		0.15	B
Vest4		0.41
MutPred		0.42		Loss of loop (P = 0.0603)
MVP		0.92
MPC		1.7
ClinPred		0.25	T
GERP RS		3.4
Varity_R		0.27
gMVP		0.65
Mutation Taster		=72/28	polymorphism

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: rs199473549; hg19: chr7-150655182;