NM_000238.4:c.3054_3055insCCCCCCCCCCCCCCCC

Variant names:

• chr7-150947425-T-TGGGGGGGGGGGGGGGG
• rs1554424138
• NM_000238.4:c.3054_3055insCCCCCCCCCCCCCCCC

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_000238.4(KCNH2):​c.3054_3055insCCCCCCCCCCCCCCCC​(p.Thr1019ProfsTer105) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P1018P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNH2 NM_000238.4 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.166
• 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), Ambry Genetics, G2P
• short QT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• 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 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	NM_000238.4	MANE Select	c.3054_3055insCCCCCCCCCCCCCCCC	p.Thr1019ProfsTer105	frameshift	Exon 13 of 15	NP_000229.1
	KCNH2	NM_001406753.1		c.2766_2767insCCCCCCCCCCCCCCCC	p.Thr923ProfsTer105	frameshift	Exon 11 of 13	NP_001393682.1
	KCNH2	NM_172057.3		c.2034_2035insCCCCCCCCCCCCCCCC	p.Thr679ProfsTer105	frameshift	Exon 9 of 11	NP_742054.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.3054_3055insCCCCCCCCCCCCCCCC	p.Thr1019ProfsTer105	frameshift	Exon 13 of 15	ENSP00000262186.5
	KCNH2	ENST00000330883.9	TSL:1	c.2034_2035insCCCCCCCCCCCCCCCC	p.Thr679ProfsTer105	frameshift	Exon 9 of 11	ENSP00000328531.4
	KCNH2	ENST00000713710.1		c.2988_2989insCCCCCCCCCCCCCCCC	p.Thr997ProfsTer105	frameshift	Exon 13 of 15	ENSP00000519013.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1287678 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 638550

African (AFR) AF: 0.00 AC: 0 AN: 29722

American (AMR) AF: 0.00 AC: 0 AN: 35468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24122

East Asian (EAS) AF: 0.00 AC: 0 AN: 33826

South Asian (SAS) AF: 0.00 AC: 0 AN: 77212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5108

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 981426

Other (OTH) AF: 0.00 AC: 0 AN: 53956

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.17

Splicing

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

Other links and lift over

dbSNP: rs1554424138; hg19: chr7-150644513;