chr7-150959622-G-C

Variant names:

• chr7-150959622-G-C
• rs199472864
• NM_000238.4:c.422C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000238.4(KCNH2):​c.422C>G​(p.Pro141Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign 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. P141L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.375
• 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 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2321482).

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.422C>G	p.Pro141Arg	missense	Exon 3 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.134C>G	p.Pro45Arg	missense	Exon 1 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172056.3		c.422C>G	p.Pro141Arg	missense	Exon 3 of 9	NP_742053.1	Q12809-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.422C>G	p.Pro141Arg	missense	Exon 3 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000713710.1		c.422C>G	p.Pro141Arg	missense	Exon 3 of 15	ENSP00000519013.1	A0AAQ5BGR0
	KCNH2	ENST00000713701.1		c.122C>G	p.Pro41Arg	missense	Exon 2 of 14	ENSP00000519004.1	A0AAQ5BGQ9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
CardioboostArm	Benign	0.00024
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.056
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.23	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.4	L
PhyloP100		0.38
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.014	D
Sift4G	Benign	0.53	T
Polyphen		0.18	B
Vest4		0.34
MutPred		0.27		Gain of solvent accessibility (P = 0.0411)
MVP		0.49
MPC		1.2
ClinPred		0.33	T
GERP RS		3.8
Varity_R		0.11
gMVP		0.63
Mutation Taster		=20/80	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: rs199472864; hg19: chr7-150656710;