Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_000238.4(KCNH2):c.51C>G(p.Thr17Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,588,116 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T17T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00080 ( 0 hom., cov: 27)

Exomes 𝑓: 0.0013 ( 3 hom. )

Consequence

KCNH2
NM_000238.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:11

Conservation

PhyloP100: 0.754

Publications

1 publications found

Variant links:

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

KCNH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 7-150977863-G-C is Benign according to our data. Variant chr7-150977863-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 200272.

BP7

Synonymous conserved (PhyloP=0.754 with no splicing effect.

BS2

High AC in GnomAd4 at 117 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNH2	NM_000238.4	MANE Select	c.51C>G	p.Thr17Thr	synonymous	Exon 1 of 15	NP_000229.1
KCNH2	NM_172056.3		c.51C>G	p.Thr17Thr	synonymous	Exon 1 of 9	NP_742053.1
KCNH2	NR_176254.1		n.459C>G		non_coding_transcript_exon	Exon 1 of 15

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.51C>G	p.Thr17Thr	synonymous	Exon 1 of 15	ENSP00000262186.5
KCNH2	ENST00000713710.1		c.51C>G	p.Thr17Thr	synonymous	Exon 1 of 15	ENSP00000519013.1
KCNH2	ENST00000532957.5	TSL:2	n.274C>G		non_coding_transcript_exon	Exon 1 of 9

Frequencies

GnomAD3 genomes

AF:

0.000800

AC:

117

AN:

146286

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000252

Gnomad AMI

AF:

0.0135

Gnomad AMR

AF:

0.000550

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:

0.00131

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000612

AC:

147

AN:

240046

AF XY:

0.000599

show subpopulations

Gnomad AFR exome

AF:

0.000475

Gnomad AMR exome

AF:

0.000293

Gnomad ASJ exome

AF:

0.000204

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00115

Gnomad OTH exome

AF:

0.000845

GnomAD4 exome

AF:

0.00127

AC:

1834

AN:

1441712

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

877

AN XY:

716482

show subpopulations

African (AFR)

AF:

0.000303

AC:

AN:

33020

American (AMR)

AF:

0.000340

AC:

AN:

44128

Ashkenazi Jewish (ASJ)

AF:

0.000196

AC:

AN:

25552

East Asian (EAS)

AF:

0.00

AC:

AN:

38710

South Asian (SAS)

AF:

0.0000583

AC:

AN:

85704

European-Finnish (FIN)

AF:

0.000100

AC:

AN:

49966

Middle Eastern (MID)

AF:

0.000411

AC:

AN:

4872

European-Non Finnish (NFE)

AF:

0.00157

AC:

1731

AN:

1100498

Other (OTH)

AF:

0.00103

AC:

AN:

59262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

168

251

335

419

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000799

AC:

117

AN:

146404

Hom.:

Cov.:

AF XY:

0.000520

AC XY:

AN XY:

71136

show subpopulations

African (AFR)

AF:

0.000251

AC:

AN:

39776

American (AMR)

AF:

0.000549

AC:

AN:

14560

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3406

East Asian (EAS)

AF:

0.00

AC:

AN:

4730

South Asian (SAS)

AF:

0.00

AC:

AN:

4594

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9512

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.00131

AC:

AN:

66628

Other (OTH)

AF:

0.00

AC:

AN:

2026

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00102

Hom.:

Bravo

AF:

0.00102

EpiCase

AF:

0.000818

EpiControl

AF:

0.00137

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (4)

Long QT syndrome (2)

Cardiac arrhythmia (1)

Cardiovascular phenotype (1)

Long QT syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

0.75

PromoterAI

0.042

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs144338227

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over