rs141401803

Variant names:

• chr7-150947711-G-A
• rs141401803
• NM_000238.4:c.2860C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PP2 PP3 BS2_Supporting

The NM_000238.4(KCNH2):​c.2860C>T​(p.Arg954Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000468 in 1,580,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R954H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7 O:1
• Conservation: PhyloP100: 1.38
• Publications: 14 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 3 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, 20 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, short QT syndrome type 1, short QT syndrome, Brugada syndrome, long QT syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783
• 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.2860C>T	p.Arg954Cys	missense	Exon 12 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.2572C>T	p.Arg858Cys	missense	Exon 10 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172057.3		c.1840C>T	p.Arg614Cys	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.2860C>T	p.Arg954Cys	missense	Exon 12 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000330883.9	TSL:1	c.1840C>T	p.Arg614Cys	missense	Exon 8 of 11	ENSP00000328531.4	Q12809-2
	KCNH2	ENST00000713710.1		c.2794C>T	p.Arg932Cys	missense	Exon 12 of 15	ENSP00000519013.1	A0AAQ5BGR0

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152156 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: 0.0000375 AC: 7 AN: 186632 AF XY: 0.0000390

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000349

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000629

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000476 AC: 68 AN: 1428058 Hom.: 0 Cov.: 36 AF XY: 0.0000410 AC XY: 29 AN XY: 708030

African (AFR) AF: 0.00 AC: 0 AN: 32892

American (AMR) AF: 0.0000249 AC: 1 AN: 40230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25562

East Asian (EAS) AF: 0.00 AC: 0 AN: 38142

South Asian (SAS) AF: 0.0000484 AC: 4 AN: 82576

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5318

European-Non Finnish (NFE) AF: 0.0000556 AC: 61 AN: 1097366

Other (OTH) AF: 0.0000338 AC: 2 AN: 59114

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152156 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74320

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

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68002

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

Alfa AF: 0.000240 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000255 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Cardiovascular phenotype (2)
-	2	-	Long QT syndrome (2)
-	1	-	Cardiac arrhythmia (1)
-	1	-	not provided (1)
-	1	-	not specified (1)
-	-	-	SUDDEN INFANT DEATH SYNDROME (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
CardioboostArm	Uncertain	0.87
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.69	N
PhyloP100		1.4
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.67
Sift	Uncertain	0.023	D
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.60
MVP		0.99
MPC		0.62
ClinPred		0.22	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.2
Varity_R		0.18
gMVP		0.67
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs141401803; hg19: chr7-150644799;