rs199473435

Variant names:

• chr7-150947854-G-A
• rs199473435
• NM_000238.4:c.2717C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-150947854-G-A
• chr7-150947854-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP2 PP5 BS2_Supporting

The NM_000238.4(KCNH2):​c.2717C>T​(p.Ser906Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000792 in 1,527,946 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S906S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:7 O:1
• Conservation: PhyloP100: 1.47
• Publications: 7 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 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.
• PP5: Variant 7-150947854-G-A is Pathogenic according to our data. Variant chr7-150947854-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 67429.
• BS2: High AC in GnomAd4 at 6 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.2717C>T	p.Ser906Leu	missense	Exon 12 of 15	NP_000229.1
	KCNH2	NM_001406753.1		c.2429C>T	p.Ser810Leu	missense	Exon 10 of 13	NP_001393682.1
	KCNH2	NM_172057.3		c.1697C>T	p.Ser566Leu	missense	Exon 8 of 11	NP_742054.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.2717C>T	p.Ser906Leu	missense	Exon 12 of 15	ENSP00000262186.5
	KCNH2	ENST00000330883.9	TSL:1	c.1697C>T	p.Ser566Leu	missense	Exon 8 of 11	ENSP00000328531.4
	KCNH2	ENST00000713710.1		c.2651C>T	p.Ser884Leu	missense	Exon 12 of 15	ENSP00000519013.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152162 Hom.: 0 Cov.: 33

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000722 AC: 9 AN: 124636 AF XY: 0.0000732

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000427

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000974

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000131

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000836 AC: 115 AN: 1375784 Hom.: 0 Cov.: 36 AF XY: 0.0000737 AC XY: 50 AN XY: 678456

African (AFR) AF: 0.0000319 AC: 1 AN: 31308

American (AMR) AF: 0.0000575 AC: 2 AN: 34764

Ashkenazi Jewish (ASJ) AF: 0.0000405 AC: 1 AN: 24686

East Asian (EAS) AF: 0.00 AC: 0 AN: 35582

South Asian (SAS) AF: 0.0000256 AC: 2 AN: 78146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34530

Middle Eastern (MID) AF: 0.000247 AC: 1 AN: 4048

European-Non Finnish (NFE) AF: 0.0000958 AC: 103 AN: 1075354

Other (OTH) AF: 0.0000872 AC: 5 AN: 57366

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74326

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000491

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	-	-	Long QT syndrome (3)
1	2	-	not provided (3)
1	1	-	Cardiovascular phenotype (2)
-	2	-	Short QT syndrome type 1;C3150943:Long QT syndrome 2 (2)
1	-	-	Cardiac arrhythmia (1)
1	-	-	Congenital long QT syndrome (2)
-	1	-	KCNH2-related disorder (1)
-	1	-	Long QT syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
CardioboostArm	Uncertain	0.85
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.37
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	0.026
Eigen_PC	Benign	0.057
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	0.69	N
PhyloP100		1.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.6	N
REVEL	Pathogenic	0.76
Sift	Benign	0.054	T
Sift4G	Benign	0.10	T
Polyphen		0.99	D
Vest4		0.29
MVP		0.99
MPC		0.15
ClinPred		0.060	T
GERP RS		4.1
Varity_R		0.13
gMVP		0.62
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs199473435; hg19: chr7-150644942; COSMIC: COSV108043934; COSMIC: COSV108043934;