dbSNP rs199473434: KCNH2:p.Thr895Met (chr7-150948452-G-A) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PS3PM1PP2PP3BS2_Supporting

The NM_000238.4(KCNH2):c.2684C>T(p.Thr895Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000301 in 1,230,738 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 Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002526383: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID:26129877" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T895K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:7O:1

Conservation

PhyloP100: 3.77

Publications

11 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), 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

KCNH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV002526383: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 26129877; 18596570)"

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, 0.81

BS2

High AC in GnomAd4 at 7 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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	UniProt
KCNH2	NM_000238.4	MANE Select	c.2684C>T	p.Thr895Met	missense	Exon 11 of 15	NP_000229.1	A0A090N8Q0
KCNH2	NM_001406753.1		c.2396C>T	p.Thr799Met	missense	Exon 9 of 13	NP_001393682.1	Q12809-7
KCNH2	NM_172057.3		c.1664C>T	p.Thr555Met	missense	Exon 7 of 11	NP_742054.1	Q12809-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.2684C>T	p.Thr895Met	missense	Exon 11 of 15	ENSP00000262186.5	Q12809-1
KCNH2	ENST00000330883.9	TSL:1	c.1664C>T	p.Thr555Met	missense	Exon 7 of 11	ENSP00000328531.4	Q12809-2
KCNH2	ENST00000713710.1		c.2618C>T	p.Thr873Met	missense	Exon 11 of 15	ENSP00000519013.1	A0AAQ5BGR0

Frequencies

GnomAD3 genomes

AF:

0.0000535

AC:

AN:

130820

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00106

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000158

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000205

AC:

AN:

243318

AF XY:

0.00000755

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000273

AC:

AN:

1099880

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

550626

show subpopulations

African (AFR)

AF:

0.0000823

AC:

AN:

24300

American (AMR)

AF:

0.00

AC:

AN:

37934

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17084

East Asian (EAS)

AF:

0.000860

AC:

AN:

18606

South Asian (SAS)

AF:

0.00

AC:

AN:

81410

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28862

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4354

European-Non Finnish (NFE)

AF:

0.0000118

AC:

AN:

846148

Other (OTH)

AF:

0.0000486

AC:

AN:

41182

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000535

AC:

AN:

130858

Hom.:

Cov.:

AF XY:

0.0000161

AC XY:

AN XY:

62152

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

35012

American (AMR)

AF:

0.000164

AC:

AN:

12208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3312

East Asian (EAS)

AF:

0.00106

AC:

AN:

3772

South Asian (SAS)

AF:

0.00

AC:

AN:

3662

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

256

European-Non Finnish (NFE)

AF:

0.0000158

AC:

AN:

63392

Other (OTH)

AF:

0.00

AC:

AN:

1838

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Long QT syndrome 2 (3)

Long QT syndrome (2)

Cardiac arrhythmia (1)

Cardiovascular phenotype (1)

Long QT syndrome 1 (1)

not provided (1)

SUDDEN INFANT DEATH SYNDROME (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

CardioboostArm

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.40

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.81

MetaSVM

Pathogenic

0.99

MutationAssessor

Benign

1.7

PhyloP100

3.8

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.5

REVEL

Pathogenic

0.76

Sift

Benign

0.17

Sift4G

Benign

0.11

Polyphen

0.98

Vest4

0.68

MVP

0.98

MPC

0.47

ClinPred

0.87

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.082

gMVP

0.72

Mutation Taster

=10/90

disease causing (ClinVar)

(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

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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

Computational scores

Splicing

Publications

Other links and lift over