NM_000238.4:c.2398+178C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000238.4(KCNH2):c.2398+178C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000171 in 1,553,936 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00081 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.0980

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005583346).

BP6

Variant 7-150949990-G-A is Benign according to our data. Variant chr7-150949990-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 191542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 124 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.2398+178C>T		intron	N/A	NP_000229.1
KCNH2	NM_172056.3		c.2576C>T	p.Thr859Met	missense	Exon 9 of 9	NP_742053.1
KCNH2	NM_001406755.1		c.2399C>T	p.Thr800Met	missense	Exon 9 of 9	NP_001393684.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.2398+178C>T	intron	N/A	ENSP00000262186.5
KCNH2	ENST00000330883.9	TSL:1	c.1378+178C>T	intron	N/A	ENSP00000328531.4
KCNH2	ENST00000461280.2	TSL:1	n.1874C>T	non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes

AF:

0.000769

AC:

117

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00258

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.000956

GnomAD2 exomes

AF:

0.000173

AC:

AN:

161984

AF XY:

0.000162

show subpopulations

Gnomad AFR exome

AF:

0.00295

Gnomad AMR exome

AF:

0.0000399

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000887

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000101

AC:

142

AN:

1401678

Hom.:

Cov.:

AF XY:

0.0000997

AC XY:

AN XY:

692194

show subpopulations

African (AFR)

AF:

0.00256

AC:

AN:

31648

American (AMR)

AF:

0.0000556

AC:

AN:

35986

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25200

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35674

South Asian (SAS)

AF:

0.0000252

AC:

AN:

79380

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49436

Middle Eastern (MID)

AF:

0.000878

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.0000444

AC:

AN:

1080580

Other (OTH)

AF:

0.0000517

AC:

AN:

58080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.000814

AC:

124

AN:

152258

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00274

AC:

114

AN:

41542

American (AMR)

AF:

0.000458

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68004

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.000533

Hom.:

Bravo

AF:

0.000899

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00130

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000714

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Cardiac arrhythmia (1)

KCNH2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.57

CADD

Benign

1.3

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.39

M_CAP

Benign

0.013

MetaRNN

Benign

0.0056

MetaSVM

Uncertain

0.25

PhyloP100

-0.098

REVEL

Benign

0.26

Sift4G

Benign

0.24

Vest4

0.15

MVP

0.082

ClinPred

0.016

GERP RS

-5.1

Mutation Taster

=99/1

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.

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