rs41314393

Variant names:

• chr7-150955521-G-A
• rs41314393
• ENST00000330883.9:c.-18C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_172057.3(KCNH2):​c.-18C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000208 in 1,537,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000079 (0 hom.)
• Consequence: KCNH2 NM_172057.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.481
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BS2: High AC in GnomAd4 at 21 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172057.3. 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.1128+1770C>T		intron	N/A	NP_000229.1
	KCNH2	NM_172057.3		c.-18C>T		5_prime_UTR	Exon 1 of 11	NP_742054.1
	KCNH2	NM_001204798.2		c.-18C>T		5_prime_UTR	Exon 1 of 5	NP_001191727.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000330883.9	TSL:1	c.-18C>T		5_prime_UTR	Exon 1 of 11	ENSP00000328531.4
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.1128+1770C>T		intron	N/A	ENSP00000262186.5
	KCNH2	ENST00000461280.2	TSL:1	n.301C>T		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152228 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000506

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000143 AC: 2 AN: 139918 AF XY: 0.00

Gnomad AFR exome AF: 0.000288

Gnomad AMR exome AF: 0.00

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: 0.00000794 AC: 11 AN: 1385584 Hom.: 0 Cov.: 31 AF XY: 0.0000117 AC XY: 8 AN XY: 681414

African (AFR) AF: 0.000255 AC: 8 AN: 31316

American (AMR) AF: 0.00 AC: 0 AN: 35402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24774

East Asian (EAS) AF: 0.00 AC: 0 AN: 35458

South Asian (SAS) AF: 0.00 AC: 0 AN: 78386

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4222

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1071350

Other (OTH) AF: 0.0000525 AC: 3 AN: 57134

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152346 Hom.: 0 Cov.: 34 AF XY: 0.000107 AC XY: 8 AN XY: 74498

African (AFR) AF: 0.000505 AC: 21 AN: 41584

American (AMR) AF: 0.00 AC: 0 AN: 15312

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

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

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000136

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	7.5
DANN	Benign	0.76
PhyloP100		-0.48
PromoterAI		-0.066	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41314393; hg19: chr7-150652609;