rs199473012

Variant names:

• chr7-150947708-G-C
• rs199473012
• NM_000238.4:c.2863C>G

Your query was ambiguous. Multiple possible variants found:

• chr7-150947708-G-C
• chr7-150947708-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PP2 PP5 BP4 BS2_Supporting

The NM_000238.4(KCNH2):​c.2863C>G​(p.Leu955Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000058 in 1,585,518 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L955P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:9 O:2
• Conservation: PhyloP100: 1.12
• Publications: 9 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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 23 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, Brugada syndrome, short QT syndrome type 1, short QT syndrome, long QT syndrome.
• PP5: Variant 7-150947708-G-C is Pathogenic according to our data. Variant chr7-150947708-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 67445.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29663557). . Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAd4 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.2863C>G	p.Leu955Val	missense	Exon 12 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.2575C>G	p.Leu859Val	missense	Exon 10 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172057.3		c.1843C>G	p.Leu615Val	missense	Exon 8 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.2863C>G	p.Leu955Val	missense	Exon 12 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000330883.9	TSL:1	c.1843C>G	p.Leu615Val	missense	Exon 8 of 11	ENSP00000328531.4	Q12809-2
	KCNH2	ENST00000713710.1		c.2797C>G	p.Leu933Val	missense	Exon 12 of 15	ENSP00000519013.1	A0AAQ5BGR0

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000257 AC: 5 AN: 194206 AF XY: 0.0000281

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000598

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000586 AC: 84 AN: 1433222 Hom.: 0 Cov.: 36 AF XY: 0.0000535 AC XY: 38 AN XY: 710940

African (AFR) AF: 0.0000303 AC: 1 AN: 33012

American (AMR) AF: 0.0000733 AC: 3 AN: 40900

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25634

East Asian (EAS) AF: 0.00 AC: 0 AN: 38444

South Asian (SAS) AF: 0.00 AC: 0 AN: 83032

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47806

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5392

European-Non Finnish (NFE) AF: 0.0000655 AC: 72 AN: 1099724

Other (OTH) AF: 0.000135 AC: 8 AN: 59278

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152296 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74462

African (AFR) AF: 0.00 AC: 0 AN: 41574

American (AMR) AF: 0.000261 AC: 4 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68000

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.0000902 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.0000338 AC: 4

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	3	-	not provided (5)
1	2	-	Long QT syndrome (4)
-	1	-	Cardiac arrhythmia (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	not specified (1)
1	-	-	Primary familial dilated cardiomyopathy (1)
-	1	-	Short QT syndrome type 1;C3150943:Long QT syndrome 2 (1)
-	-	-	Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
CardioboostArm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Benign	0.054
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.30	T
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Benign	0.90	L
PhyloP100		1.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.97	N
REVEL	Uncertain	0.60
Sift	Benign	0.24	T
Sift4G	Benign	0.16	T
Polyphen		0.51	P
Vest4		0.27
MVP		0.96
MPC		0.63
ClinPred		0.40	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.2
Varity_R		0.21
gMVP		0.59
Mutation Taster		=17/83	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199473012; hg19: chr7-150644796;