rs1805120

Variant names:

• chr7-150952443-G-A
• rs1805120
• NM_000238.4:c.1539C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000238.4(KCNH2):​c.1539C>T​(p.Phe513Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,613,742 control chromosomes in the GnomAD database, including 55,335 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5902 hom., cov: 33)
  • Exomes 𝑓: 0.24 (49433 hom.)
• Consequence: KCNH2 NM_000238.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -1.68
• Publications: 40 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 7-150952443-G-A is Benign according to our data. Variant chr7-150952443-G-A is described in ClinVar as Benign. ClinVar VariationId is 36428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.68 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.634 is higher than 0.05.

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.1539C>T	p.Phe513Phe	synonymous	Exon 6 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.1251C>T	p.Phe417Phe	synonymous	Exon 4 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172056.3		c.1539C>T	p.Phe513Phe	synonymous	Exon 6 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.1539C>T	p.Phe513Phe	synonymous	Exon 6 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000330883.9	TSL:1	c.519C>T	p.Phe173Phe	synonymous	Exon 2 of 11	ENSP00000328531.4	Q12809-2
	KCNH2	ENST00000461280.2	TSL:1	n.837C>T		non_coding_transcript_exon	Exon 2 of 5

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39774 AN: 151974 Hom.: 5887 Cov.: 33

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.271

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.337

Gnomad EAS AF: 0.652

Gnomad SAS AF: 0.313

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.262

GnomAD2 exomes AF: 0.302 AC: 75720 AN: 250862 AF XY: 0.296

Gnomad AFR exome AF: 0.246

Gnomad AMR exome AF: 0.406

Gnomad ASJ exome AF: 0.327

Gnomad EAS exome AF: 0.656

Gnomad FIN exome AF: 0.310

Gnomad NFE exome AF: 0.215

Gnomad OTH exome AF: 0.292

GnomAD4 exome AF: 0.244 AC: 355943 AN: 1461650 Hom.: 49433 Cov.: 39 AF XY: 0.246 AC XY: 178821 AN XY: 727136

African (AFR) AF: 0.248 AC: 8308 AN: 33474

American (AMR) AF: 0.397 AC: 17724 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 8492 AN: 26132

East Asian (EAS) AF: 0.680 AC: 26996 AN: 39694

South Asian (SAS) AF: 0.316 AC: 27240 AN: 86252

European-Finnish (FIN) AF: 0.297 AC: 15876 AN: 53388

Middle Eastern (MID) AF: 0.270 AC: 1558 AN: 5768

European-Non Finnish (NFE) AF: 0.210 AC: 233528 AN: 1111878

Other (OTH) AF: 0.269 AC: 16221 AN: 60388

GnomAD4 genome AF: 0.262 AC: 39815 AN: 152092 Hom.: 5902 Cov.: 33 AF XY: 0.270 AC XY: 20108 AN XY: 74340

African (AFR) AF: 0.243 AC: 10086 AN: 41478

American (AMR) AF: 0.329 AC: 5027 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.337 AC: 1168 AN: 3468

East Asian (EAS) AF: 0.652 AC: 3371 AN: 5170

South Asian (SAS) AF: 0.315 AC: 1517 AN: 4822

European-Finnish (FIN) AF: 0.315 AC: 3328 AN: 10568

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.212 AC: 14430 AN: 67990

Other (OTH) AF: 0.269 AC: 566 AN: 2106

Alfa AF: 0.240 Hom.: 3273

Bravo AF: 0.267

Asia WGS AF: 0.451 AC: 1566 AN: 3478

EpiCase AF: 0.225

EpiControl AF: 0.219

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Long QT syndrome (3)
-	-	2	Cardiac arrhythmia (2)
-	-	2	Long QT syndrome 2 (2)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.45
DANN	Benign	0.76
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs1805120; hg19: chr7-150649531; COSMIC: COSV100059241;