rs140743924

Variant names:

• chr7-150948512-G-A
• rs140743924
• NM_000238.4:c.2624C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-150948512-G-A
• chr7-150948512-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_000238.4(KCNH2):​c.2624C>T​(p.Thr875Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000224 in 1,565,862 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T875P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5 O:1
• Conservation: PhyloP100: 2.30
• Publications: 5 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_benign. The variant received -4 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=0.2757076).
• BS2: High AC in GnomAdExome4 at 31 AD gene.

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.2624C>T	p.Thr875Met	missense	Exon 11 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.2336C>T	p.Thr779Met	missense	Exon 9 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172057.3		c.1604C>T	p.Thr535Met	missense	Exon 7 of 11	NP_742054.1	Q12809-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.2624C>T	p.Thr875Met	missense	Exon 11 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000330883.9	TSL:1	c.1604C>T	p.Thr535Met	missense	Exon 7 of 11	ENSP00000328531.4	Q12809-2
	KCNH2	ENST00000713710.1		c.2558C>T	p.Thr853Met	missense	Exon 11 of 15	ENSP00000519013.1	A0AAQ5BGR0

Frequencies

GnomAD3 genomes AF: 0.0000269 AC: 4 AN: 148564 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000247

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: 0.0000446

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250496 AF XY: 0.00000738

Gnomad AFR exome AF: 0.0000617

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 31 AN: 1417298 Hom.: 0 Cov.: 37 AF XY: 0.0000241 AC XY: 17 AN XY: 704740

African (AFR) AF: 0.00 AC: 0 AN: 31928

American (AMR) AF: 0.00 AC: 0 AN: 43286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24414

East Asian (EAS) AF: 0.0000276 AC: 1 AN: 36262

South Asian (SAS) AF: 0.0000582 AC: 5 AN: 85850

European-Finnish (FIN) AF: 0.0000202 AC: 1 AN: 49578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5504

European-Non Finnish (NFE) AF: 0.0000203 AC: 22 AN: 1083132

Other (OTH) AF: 0.0000349 AC: 2 AN: 57344

GnomAD4 genome AF: 0.0000269 AC: 4 AN: 148564 Hom.: 0 Cov.: 31 AF XY: 0.0000276 AC XY: 2 AN XY: 72354

African (AFR) AF: 0.0000247 AC: 1 AN: 40466

American (AMR) AF: 0.00 AC: 0 AN: 14872

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 4766

South Asian (SAS) AF: 0.00 AC: 0 AN: 4456

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9954

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000446 AC: 3 AN: 67328

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.0000319 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
CardioboostArm	Benign	0.0000017
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.28	T
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Benign	0.69	N
PhyloP100		2.3
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.42
Sift	Benign	0.13	T
Sift4G	Benign	0.098	T
Polyphen		1.0	D
Vest4		0.24
MVP		0.84
MPC		0.24
ClinPred		0.076	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.024
gMVP		0.58
Mutation Taster		=87/13	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: rs140743924; hg19: chr7-150645600;