rs36210421

Variant names:

• chr7-150947340-C-A
• rs36210421
• NM_000238.4:c.3140G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-150947340-C-A
• chr7-150947340-C-T
• chr7-150947340-C-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_000238.4(KCNH2):​c.3140G>T​(p.Arg1047Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0211 in 1,542,350 control chromosomes in the GnomAD database, including 511 homozygotes. 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. R1047H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.018 (61 hom., cov: 33)
  • Exomes 𝑓: 0.021 (450 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:15 O:1
• Conservation: PhyloP100: -0.147
• Publications: 55 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: Benign. The variant received -12 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=0.0038214326).
• BP6: Variant 7-150947340-C-A is Benign according to our data. Variant chr7-150947340-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36429.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0183 (2780/152138) while in subpopulation NFE AF = 0.0259 (1758/67958). AF 95% confidence interval is 0.0249. There are 61 homozygotes in GnomAd4. There are 1492 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2780 AD gene.

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.3140G>T	p.Arg1047Leu	missense	Exon 13 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.2852G>T	p.Arg951Leu	missense	Exon 11 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172057.3		c.2120G>T	p.Arg707Leu	missense	Exon 9 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.3140G>T	p.Arg1047Leu	missense	Exon 13 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000330883.9	TSL:1	c.2120G>T	p.Arg707Leu	missense	Exon 9 of 11	ENSP00000328531.4	Q12809-2
	KCNH2	ENST00000713710.1		c.3074G>T	p.Arg1025Leu	missense	Exon 13 of 15	ENSP00000519013.1	A0AAQ5BGR0

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2781 AN: 152020 Hom.: 61 Cov.: 33

Gnomad AFR AF: 0.00316

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.0695

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0259

Gnomad OTH AF: 0.00814

GnomAD2 exomes AF: 0.0161 AC: 2282 AN: 141590 AF XY: 0.0154

Gnomad AFR exome AF: 0.00379

Gnomad AMR exome AF: 0.00406

Gnomad ASJ exome AF: 0.00429

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0732

Gnomad NFE exome AF: 0.0228

Gnomad OTH exome AF: 0.0123

GnomAD4 exome AF: 0.0214 AC: 29701 AN: 1390212 Hom.: 450 Cov.: 35 AF XY: 0.0207 AC XY: 14205 AN XY: 685964

African (AFR) AF: 0.00304 AC: 96 AN: 31604

American (AMR) AF: 0.00432 AC: 154 AN: 35642

Ashkenazi Jewish (ASJ) AF: 0.00382 AC: 96 AN: 25118

East Asian (EAS) AF: 0.00 AC: 0 AN: 35766

South Asian (SAS) AF: 0.00364 AC: 288 AN: 79070

European-Finnish (FIN) AF: 0.0704 AC: 2922 AN: 41486

Middle Eastern (MID) AF: 0.00675 AC: 35 AN: 5182

European-Non Finnish (NFE) AF: 0.0234 AC: 25255 AN: 1078506

Other (OTH) AF: 0.0148 AC: 855 AN: 57838

GnomAD4 genome AF: 0.0183 AC: 2780 AN: 152138 Hom.: 61 Cov.: 33 AF XY: 0.0201 AC XY: 1492 AN XY: 74392

African (AFR) AF: 0.00315 AC: 131 AN: 41534

American (AMR) AF: 0.00477 AC: 73 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4820

European-Finnish (FIN) AF: 0.0695 AC: 737 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0259 AC: 1758 AN: 67958

Other (OTH) AF: 0.00806 AC: 17 AN: 2110

Alfa AF: 0.0148 Hom.: 18

Bravo AF: 0.0125

TwinsUK AF: 0.0202 AC: 75

ALSPAC AF: 0.0236 AC: 91

ESP6500AA AF: 0.00419 AC: 16

ESP6500EA AF: 0.0178 AC: 139

ExAC AF: 0.00738 AC: 670

Asia WGS AF: 0.00404 AC: 15 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Long QT syndrome (3)
-	-	3	not provided (4)
-	-	3	not specified (3)
-	1	1	Long QT syndrome 2 (2)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	KCNH2-related disorder (1)
-	-	1	Sudden unexplained death (1)
-	-	1	Torsades de pointes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.40	N
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.15
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.60
Sift	Benign	0.054	T
Sift4G	Benign	0.34	T
Polyphen		0.065	B
Vest4		0.53
MPC		0.45
ClinPred		0.030	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.50
Mutation Taster		=97/3	polymorphism (auto)

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: rs36210421; hg19: chr7-150644428; COSMIC: COSV51212069; COSMIC: COSV51212069;