7-150959718-A-C

Variant names:

• chr7-150959718-A-C
• rs199473498
• NM_000238.4:c.326T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 9P and 2B. PM1 PM2 PP2 PP3_Strong BP6_Moderate

The NM_000238.4(KCNH2):​c.326T>G​(p.Leu109Arg) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L109Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 3.46
• Publications: 3 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 18 uncertain in NM_000238.4
• 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, 0.964
• BP6: Variant 7-150959718-A-C is Benign according to our data. Variant chr7-150959718-A-C is described in ClinVar as Benign. ClinVar VariationId is 67484.Status of the report is criteria_provided_single_submitter, 1 stars.

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.326T>G	p.Leu109Arg	missense	Exon 3 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.38T>G	p.Leu13Arg	missense	Exon 1 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172056.3		c.326T>G	p.Leu109Arg	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.326T>G	p.Leu109Arg	missense	Exon 3 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000713710.1		c.326T>G	p.Leu109Arg	missense	Exon 3 of 15	ENSP00000519013.1	A0AAQ5BGR0
	KCNH2	ENST00000713701.1		c.26T>G	p.Leu9Arg	missense	Exon 2 of 14	ENSP00000519004.1	A0AAQ5BGQ9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Long QT syndrome 2 (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
CardioboostArm	Benign	0.0036
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	27
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.80	D
Eigen	Benign	-0.14
Eigen_PC	Benign	0.026
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.3	L
PhyloP100		3.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.71
Sift	Benign	0.63	T
Sift4G	Benign	0.60	T
Polyphen		0.0010	B
Vest4		0.75
MutPred		0.92		Loss of sheet (P = 0.0817)
MVP		1.0
MPC		1.4
ClinPred		0.59	D
GERP RS		4.8
Varity_R		0.75
gMVP		0.98
Mutation Taster		=5/95	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: rs199473498; hg19: chr7-150656806;