rs546898924

Variant names:

• chr7-150950062-AG-A
• rs546898924
• NM_000238.4:c.2398+105delC

Your query was ambiguous. Multiple possible variants found:

• chr7-150950062-AG-A
• chr7-150950062-AG-AGG

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PVS1_Moderate BP6 BS2

The NM_172056.3(KCNH2):​c.2503delC​(p.Leu835CysfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,612,160 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00093 (1 hom., cov: 31)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: KCNH2 NM_172056.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.158
• Publications: 4 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_benign. The variant received -3 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0615 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BP6: Variant 7-150950062-AG-A is Benign according to our data. Variant chr7-150950062-AG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 200237.
• BS2: High AC in GnomAd4 at 142 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172056.3. 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.2398+105delC		intron	N/A	NP_000229.1
	KCNH2	NM_172056.3		c.2503delC	p.Leu835CysfsTer8	frameshift	Exon 9 of 9	NP_742053.1
	KCNH2	NM_001406755.1		c.2326delC	p.Leu776CysfsTer8	frameshift	Exon 9 of 9	NP_001393684.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.2398+105delC		intron	N/A	ENSP00000262186.5
	KCNH2	ENST00000330883.9	TSL:1	c.1378+105delC		intron	N/A	ENSP00000328531.4
	KCNH2	ENST00000461280.2	TSL:1	n.1801delC		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes AF: 0.000933 AC: 142 AN: 152148 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00304

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000162 AC: 40 AN: 246520 AF XY: 0.000119

Gnomad AFR exome AF: 0.00249

Gnomad AMR exome AF: 0.0000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000747 AC: 109 AN: 1459894 Hom.: 0 Cov.: 31 AF XY: 0.0000565 AC XY: 41 AN XY: 726198

African (AFR) AF: 0.00257 AC: 86 AN: 33438

American (AMR) AF: 0.0000898 AC: 4 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 85558

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53298

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111230

Other (OTH) AF: 0.000282 AC: 17 AN: 60320

GnomAD4 genome AF: 0.000933 AC: 142 AN: 152266 Hom.: 1 Cov.: 31 AF XY: 0.000927 AC XY: 69 AN XY: 74468

African (AFR) AF: 0.00303 AC: 126 AN: 41556

American (AMR) AF: 0.000784 AC: 12 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.0000678 Hom.: 0

Bravo AF: 0.000880

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Cardiac arrhythmia (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.16
Mutation Taster		=175/25	polymorphism

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: rs546898924; hg19: chr7-150647150;