NM_000238.4:c.560_568dupGCGCGGGCG

Variant names:

• chr7-150958406-G-GCGCCCGCGC
• rs551056698
• NM_000238.4:c.560_568dupGCGCGGGCG

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM4 BS2

The NM_000238.4(KCNH2):​c.560_568dupGCGCGGGCG​(p.Gly187_Gly189dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,447,572 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: KCNH2 NM_000238.4 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 1.90
• 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_benign. The variant received -2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000238.4.
• BS2: High AC in GnomAd4 at 10 AD gene.

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.560_568dupGCGCGGGCG	p.Gly187_Gly189dup	conservative_inframe_insertion	Exon 4 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.272_280dupGCGCGGGCG	p.Gly91_Gly93dup	conservative_inframe_insertion	Exon 2 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172056.3		c.560_568dupGCGCGGGCG	p.Gly187_Gly189dup	conservative_inframe_insertion	Exon 4 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.560_568dupGCGCGGGCG	p.Gly187_Gly189dup	conservative_inframe_insertion	Exon 4 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000713710.1		c.560_568dupGCGCGGGCG	p.Gly187_Gly189dup	conservative_inframe_insertion	Exon 4 of 15	ENSP00000519013.1	A0AAQ5BGR0
	KCNH2	ENST00000713701.1		c.260_268dupGCGCGGGCG	p.Gly87_Gly89dup	conservative_inframe_insertion	Exon 3 of 14	ENSP00000519004.1	A0AAQ5BGQ9

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 151902 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

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: 0.0000951

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000159 AC: 206 AN: 1295562 Hom.: 0 Cov.: 32 AF XY: 0.000139 AC XY: 89 AN XY: 638444

African (AFR) AF: 0.00 AC: 0 AN: 25746

American (AMR) AF: 0.00 AC: 0 AN: 20902

Ashkenazi Jewish (ASJ) AF: 0.0000461 AC: 1 AN: 21680

East Asian (EAS) AF: 0.0000357 AC: 1 AN: 27998

South Asian (SAS) AF: 0.0000145 AC: 1 AN: 68738

European-Finnish (FIN) AF: 0.000154 AC: 5 AN: 32462

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4216

European-Non Finnish (NFE) AF: 0.000186 AC: 194 AN: 1040372

Other (OTH) AF: 0.0000748 AC: 4 AN: 53448

GnomAD4 genome AF: 0.0000658 AC: 10 AN: 152010 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74332

African (AFR) AF: 0.0000482 AC: 2 AN: 41532

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000951 AC: 1 AN: 10510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67934

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Cardiac arrhythmia (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Long QT syndrome (1)
-	1	-	Long QT syndrome 2 (1)
-	1	-	Short QT syndrome type 1;C3150943:Long QT syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=62/38	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs551056698; hg19: chr7-150655494;