rs754883792

Variant names:

• chr7-150945397-G-T
• rs754883792
• NM_000238.4:c.3448C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2 BP4 BS1_Supporting BS2

The ENST00000262186.10(KCNH2):​c.3448C>A​(p.Leu1150Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000221 in 1,587,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: KCNH2 ENST00000262186.10 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 2.23
• Publications: 1 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 -5 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 158 curated pathogenic missense variants (we use a threshold of 10). The gene has 38 curated benign missense variants. Gene score misZ: 3.3724 (above the threshold of 3.09). Trascript score misZ: 2.4846 (below the threshold of 3.09). GenCC associations: The gene is linked to long QT syndrome 2, Brugada syndrome, short QT syndrome type 1, short QT syndrome, long QT syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3292657).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000237 (34/1434894) while in subpopulation MID AF = 0.00459 (25/5448). AF 95% confidence interval is 0.00319. There are 0 homozygotes in GnomAdExome4. There are 21 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 34 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000262186.10. 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.3448C>A	p.Leu1150Met	missense	Exon 15 of 15	NP_000229.1
	KCNH2	NM_001406753.1		c.3160C>A	p.Leu1054Met	missense	Exon 13 of 13	NP_001393682.1
	KCNH2	NM_172057.3		c.2428C>A	p.Leu810Met	missense	Exon 11 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.3448C>A	p.Leu1150Met	missense	Exon 15 of 15	ENSP00000262186.5
	KCNH2	ENST00000330883.9	TSL:1	c.2428C>A	p.Leu810Met	missense	Exon 11 of 11	ENSP00000328531.4
	KCNH2	ENST00000713710.1		c.3382C>A	p.Leu1128Met	missense	Exon 15 of 15	ENSP00000519013.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000551 AC: 11 AN: 199644 AF XY: 0.0000925

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000111

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.0000237 AC: 34 AN: 1434894 Hom.: 0 Cov.: 31 AF XY: 0.0000295 AC XY: 21 AN XY: 711284

African (AFR) AF: 0.00 AC: 0 AN: 33004

American (AMR) AF: 0.00 AC: 0 AN: 41390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25596

East Asian (EAS) AF: 0.00 AC: 0 AN: 38394

South Asian (SAS) AF: 0.0000365 AC: 3 AN: 82232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50476

Middle Eastern (MID) AF: 0.00459 AC: 25 AN: 5448

European-Non Finnish (NFE) AF: 0.00000273 AC: 3 AN: 1099088

Other (OTH) AF: 0.0000506 AC: 3 AN: 59266

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74370

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000528 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000750 AC: 9

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Long QT syndrome (2)
-	1	1	not provided (2)
-	1	-	Cardiac arrhythmia (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	KCNH2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
CardioboostArm	Benign	0.021
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.33	T
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	1.5	L
PhyloP100		2.2
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.61	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.024	D
Sift4G	Benign	0.15	T
Polyphen		0.98	D
Vest4		0.31
MutPred		0.19		Gain of MoRF binding (P = 0.1565)
MVP		0.66
MPC		0.66
ClinPred		0.14	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.15
Mutation Taster		=61/39	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: rs754883792; hg19: chr7-150642485;