7-150948452-G-C

Variant names:

• chr7-150948452-G-C
• rs199473434
• NM_000238.4:c.2684C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1 PP2 PP3 BS2

The NM_000238.4(KCNH2):​c.2684C>G​(p.Thr895Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00002 in 1,099,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. T895M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000031 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000020 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 3.77
• Publications: 11 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: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 34 uncertain in NM_000238.4
• 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, short QT syndrome type 1, short QT syndrome, Brugada syndrome, long QT syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822
• BS2: High AC in GnomAdExome4 at 22 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.2684C>G	p.Thr895Arg	missense	Exon 11 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.2396C>G	p.Thr799Arg	missense	Exon 9 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172057.3		c.1664C>G	p.Thr555Arg	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.2684C>G	p.Thr895Arg	missense	Exon 11 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000330883.9	TSL:1	c.1664C>G	p.Thr555Arg	missense	Exon 7 of 11	ENSP00000328531.4	Q12809-2
	KCNH2	ENST00000713710.1		c.2618C>G	p.Thr873Arg	missense	Exon 11 of 15	ENSP00000519013.1	A0AAQ5BGR0

Frequencies

GnomAD3 genomes AF: 0.0000306 AC: 4 AN: 130814 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000286

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000265

Gnomad SAS AF: 0.000273

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000158

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000411 AC: 1 AN: 243318 AF XY: 0.00000755

Gnomad AFR exome AF: 0.00

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: 0.0000200 AC: 22 AN: 1099860 Hom.: 0 Cov.: 35 AF XY: 0.0000218 AC XY: 12 AN XY: 550614

African (AFR) AF: 0.00 AC: 0 AN: 24300

American (AMR) AF: 0.00 AC: 0 AN: 37934

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17082

East Asian (EAS) AF: 0.0000538 AC: 1 AN: 18604

South Asian (SAS) AF: 0.0000369 AC: 3 AN: 81410

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28862

Middle Eastern (MID) AF: 0.000230 AC: 1 AN: 4354

European-Non Finnish (NFE) AF: 0.0000165 AC: 14 AN: 846134

Other (OTH) AF: 0.0000729 AC: 3 AN: 41180

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000306 AC: 4 AN: 130814 Hom.: 0 Cov.: 30 AF XY: 0.0000483 AC XY: 3 AN XY: 62116

African (AFR) AF: 0.0000286 AC: 1 AN: 34980

American (AMR) AF: 0.00 AC: 0 AN: 12188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3312

East Asian (EAS) AF: 0.000265 AC: 1 AN: 3774

South Asian (SAS) AF: 0.000273 AC: 1 AN: 3662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.0000158 AC: 1 AN: 63388

Other (OTH) AF: 0.00 AC: 0 AN: 1828

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

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	-	Long QT syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
CardioboostArm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Benign	1.4	L
PhyloP100		3.8
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.4	N
REVEL	Pathogenic	0.69
Sift	Benign	0.45	T
Sift4G	Benign	0.62	T
Polyphen		0.80	P
Vest4		0.59
MutPred		0.39		Loss of phosphorylation at T895 (P = 6e-04)
MVP		0.99
MPC		0.48
ClinPred		0.80	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.23
gMVP		0.81
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199473434; hg19: chr7-150645540;