rs1554425226

Variant names:

• chr7-150950248-CCAGCATGCACCAGTGTGTCCCCTGGCGGTGCATGTGTGGTCTTGAACTTCATGGCCAGGGCCCGAAGGCAGCCCTTGGTGGCCCCTCGGAAGGGTTTGCAGTGCTGCAGCAGTGAGCGGTTCAGGTGCAGGCAGATGT-C
• rs1554425226
• NM_000238.4:c.2180_2317del

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM4 PP3 PP5_Moderate

The NM_000238.4(KCNH2):​c.2180_2317del​(p.Asp727_Ala772del) variant causes a disruptive inframe deletion change involving the alteration of a 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 DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: KCNH2 NM_000238.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 10.0
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000238.4
• PM4: Nonframeshift variant in NON repetitive region in NM_000238.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 7-150950248-CCAGCATGCACCAGTGTGTCCCCTGGCGGTGCATGTGTGGTCTTGAACTTCATGGCCAGGGCCCGAAGGCAGCCCTTGGTGGCCCCTCGGAAGGGTTTGCAGTGCTGCAGCAGTGAGCGGTTCAGGTGCAGGCAGATGT-C is Pathogenic according to our data. Variant chr7-150950248-CCAGCATGCACCAGTGTGTCCCCTGGCGGTGCATGTGTGGTCTTGAACTTCATGGCCAGGGCCCGAAGGCAGCCCTTGGTGGCCCCTCGGAAGGGTTTGCAGTGCTGCAGCAGTGAGCGGTTCAGGTGCAGGCAGATGT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 456903.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.2180_2317del	p.Asp727_Ala772del	disruptive_inframe_deletion	Exon 9 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.1892_2029del	p.Asp631_Ala676del	disruptive_inframe_deletion	Exon 7 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172056.3		c.2180_2317del	p.Asp727_Ala772del	disruptive_inframe_deletion	Exon 9 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.2180_2317del	p.Asp727_Ala772del	disruptive_inframe_deletion	Exon 9 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000330883.9	TSL:1	c.1160_1297del	p.Asp387_Ala432del	disruptive_inframe_deletion	Exon 5 of 11	ENSP00000328531.4	Q12809-2
	KCNH2	ENST00000461280.2	TSL:1	n.1478_1615del		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes Cov.: 30

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

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=10/190	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1554425226; hg19: chr7-150647336;