NM_000238.4:c.1764C>A

Variant names:

• chr7-150951629-G-T
• rs104894021
• NM_000238.4:c.1764C>A

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS1 PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000238.4(KCNH2):​c.1764C>A​(p.Asn588Lys) 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 Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV005600613: "In multiple assays testing KCNH2 function, this variant showed functionally abnormal results (Brugada R et al. Circulation, 2004 Jan" and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N588D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 0.270
• Publications: 132 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: Pathogenic. The variant received 21 ACMG points.

• PS1: Transcript NM_000238.4 (KCNH2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV005600613: "In multiple assays testing KCNH2 function, this variant showed functionally abnormal results (Brugada R et al. Circulation, 2004 Jan;109:30-5; Grunnet M et al. Cell Physiol Biochem, 2008 Dec;22:611-24; McPate MJ et al. J Physiol Pharmacol, 2009 Mar;60:23-41; Adeniran I et al. PLoS Comput Biol, 2011 Dec;7:e1002313)."
• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 22 uncertain in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150951631-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 67266.
• 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, 0.968
• PP5: Variant 7-150951629-G-T is Pathogenic according to our data. Variant chr7-150951629-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 14437.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.1764C>A	p.Asn588Lys	missense	Exon 7 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.1476C>A	p.Asn492Lys	missense	Exon 5 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172056.3		c.1764C>A	p.Asn588Lys	missense	Exon 7 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.1764C>A	p.Asn588Lys	missense	Exon 7 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000330883.9	TSL:1	c.744C>A	p.Asn248Lys	missense	Exon 3 of 11	ENSP00000328531.4	Q12809-2
	KCNH2	ENST00000461280.2	TSL:1	n.1062C>A		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Cardiovascular phenotype (1)
1	-	-	Short QT syndrome type 1 (1)
-	-	-	Short QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
CardioboostArm	Benign	0.0021
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Benign	0.65	N
PhyloP100		0.27
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.60
Sift	Benign	0.59	T
Sift4G	Benign	0.78	T
Polyphen		0.014	B
Vest4		0.82
MutPred		0.89		Gain of ubiquitination at N588 (P = 0.0325)
MVP		0.91
MPC		2.0
ClinPred		0.75	D
GERP RS		4.3
Varity_R		0.45
gMVP		0.91
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs104894021; hg19: chr7-150648717;