NM_000238.4:c.26C>G

Variant names:

• chr7-150977888-G-C
• rs775317201
• NM_000238.4:c.26C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000238.4(KCNH2):​c.26C>G​(p.Ala9Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,856 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A9V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.29
• 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), 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.

• 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.

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.26C>G	p.Ala9Gly	missense	Exon 1 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_172056.3		c.26C>G	p.Ala9Gly	missense	Exon 1 of 9	NP_742053.1	Q12809-5
	KCNH2	NR_176254.1		n.434C>G		non_coding_transcript_exon	Exon 1 of 15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.26C>G	p.Ala9Gly	missense	Exon 1 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000713710.1		c.26C>G	p.Ala9Gly	missense	Exon 1 of 15	ENSP00000519013.1	A0AAQ5BGR0
	KCNH2	ENST00000945647.1		c.26C>G	p.Ala9Gly	missense	Exon 1 of 14	ENSP00000615706.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455856 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 724150

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

African (AFR) AF: 0.00 AC: 0 AN: 33198

American (AMR) AF: 0.00 AC: 0 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26008

East Asian (EAS) AF: 0.00 AC: 0 AN: 39496

South Asian (SAS) AF: 0.00 AC: 0 AN: 85812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5072

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110320

Other (OTH) AF: 0.00 AC: 0 AN: 60112

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
CardioboostArm	Uncertain	0.16
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.72	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Pathogenic	1.3	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.022	D
Polyphen		0.068	B
Vest4		0.20
MutPred		0.47		Gain of disorder (P = 0.0645)
MVP		0.85
MPC		1.2
ClinPred		0.78	D
GERP RS		2.5
PromoterAI		0.051	Neutral
Varity_R		0.25
gMVP		0.80
Mutation Taster		=23/77	disease causing

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: rs775317201; hg19: chr7-150674976;