rs1554424085

Variant names:

• chr7-150947384-CCGACCCGGG-GC
• rs1554424085
• NM_000238.4:c.3087_3096delCCCGGGTCGGinsGC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000238.4(KCNH2):​c.3087_3096delCCCGGGTCGGinsGC​(p.Ser1029ArgfsTer87) variant causes a frameshift, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNH2 NM_000238.4 frameshift, synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 0.877
• 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-150947384-CCGACCCGGG-GC is Pathogenic according to our data. Variant chr7-150947384-CCGACCCGGG-GC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 526924.

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.3087_3096delCCCGGGTCGGinsGC	p.Ser1029ArgfsTer87	frameshift synonymous	Exon 13 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.2799_2808delCCCGGGTCGGinsGC	p.Ser933ArgfsTer87	frameshift synonymous	Exon 11 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172057.3		c.2067_2076delCCCGGGTCGGinsGC	p.Ser689ArgfsTer87	frameshift synonymous	Exon 9 of 11	NP_742054.1	Q12809-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.3087_3096delCCCGGGTCGGinsGC	p.Ser1029ArgfsTer87	frameshift synonymous	Exon 13 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000330883.9	TSL:1	c.2067_2076delCCCGGGTCGGinsGC	p.Ser689ArgfsTer87	frameshift synonymous	Exon 9 of 11	ENSP00000328531.4	Q12809-2
	KCNH2	ENST00000713710.1		c.3021_3030delCCCGGGTCGGinsGC	p.Ser1007ArgfsTer87	frameshift synonymous	Exon 13 of 15	ENSP00000519013.1	A0AAQ5BGR0

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.88

Splicing

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

Other links and lift over

dbSNP: rs1554424085; hg19: chr7-150644472;