rs202194495

Variant names:

• chr7-150948482-C-G
• rs202194495
• NM_000238.4:c.2654G>C

Your query was ambiguous. Multiple possible variants found:

• chr7-150948482-C-G
• chr7-150948482-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_000238.4(KCNH2):​c.2654G>C​(p.Arg885Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000675 in 148,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R885C) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000067 (0 hom., cov: 31)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.41
• Publications: 0 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 4 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	NM_000238.4	MANE Select	c.2654G>C	p.Arg885Pro	missense	Exon 11 of 15	NP_000229.1
	KCNH2	NM_001406753.1		c.2366G>C	p.Arg789Pro	missense	Exon 9 of 13	NP_001393682.1
	KCNH2	NM_172057.3		c.1634G>C	p.Arg545Pro	missense	Exon 7 of 11	NP_742054.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.2654G>C	p.Arg885Pro	missense	Exon 11 of 15	ENSP00000262186.5
	KCNH2	ENST00000330883.9	TSL:1	c.1634G>C	p.Arg545Pro	missense	Exon 7 of 11	ENSP00000328531.4
	KCNH2	ENST00000713710.1		c.2588G>C	p.Arg863Pro	missense	Exon 11 of 15	ENSP00000519013.1

Frequencies

GnomAD3 genomes AF: 0.00000675 AC: 1 AN: 148210 Hom.: 0 Cov.: 31

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: 0.000102

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249432 AF XY: 0.00000740

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: 0.0000485

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 37

GnomAD4 genome AF: 0.00000675 AC: 1 AN: 148210 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 1 AN XY: 72246

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 40608

American (AMR) AF: 0.00 AC: 0 AN: 14940

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3426

East Asian (EAS) AF: 0.00 AC: 0 AN: 4710

South Asian (SAS) AF: 0.00 AC: 0 AN: 4390

European-Finnish (FIN) AF: 0.000102 AC: 1 AN: 9780

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67080

Other (OTH) AF: 0.00 AC: 0 AN: 2064

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
CardioboostArm	Benign	0.016
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	L
PhyloP100		5.4
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.78
Sift	Benign	0.030	D
Sift4G	Benign	0.077	T
Polyphen		0.94	P
Vest4		0.74
MutPred		0.44		Loss of helix (P = 0.0072)
MVP		0.99
MPC		0.80
ClinPred		0.95	D
GERP RS		4.1
Varity_R		0.71
gMVP		0.89
Mutation Taster		=8/92	disease causing

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: rs202194495; hg19: chr7-150645570;