dbSNP rs740952: KCNH2:p.Ile489Ile (chr7-150952515-G-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000238.4(KCNH2):c.1467C>T(p.Ile489Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.246 in 1,613,896 control chromosomes in the GnomAD database, including 55,477 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I489I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.26 ( 5975 hom., cov: 32)

Exomes 𝑓: 0.24 ( 49502 hom. )

Consequence

KCNH2
NM_000238.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -0.955

Publications

33 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 7-150952515-G-A is Benign according to our data. Variant chr7-150952515-G-A is described in ClinVar as Benign. ClinVar VariationId is 255614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.955 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.627 is higher than 0.05.

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.1467C>T	p.Ile489Ile	synonymous	Exon 6 of 15	NP_000229.1
KCNH2	NM_001406753.1		c.1179C>T	p.Ile393Ile	synonymous	Exon 4 of 13	NP_001393682.1
KCNH2	NM_172056.3		c.1467C>T	p.Ile489Ile	synonymous	Exon 6 of 9	NP_742053.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.1467C>T	p.Ile489Ile	synonymous	Exon 6 of 15	ENSP00000262186.5
KCNH2	ENST00000330883.9	TSL:1	c.447C>T	p.Ile149Ile	synonymous	Exon 2 of 11	ENSP00000328531.4
KCNH2	ENST00000461280.2	TSL:1	n.765C>T		non_coding_transcript_exon	Exon 2 of 5

Frequencies

GnomAD3 genomes

AF:

0.265

AC:

40214

AN:

151916

Hom.:

5956

Cov.:

show subpopulations

Gnomad AFR

AF:

0.255

Gnomad AMI

AF:

0.272

Gnomad AMR

AF:

0.331

Gnomad ASJ

AF:

0.337

Gnomad EAS

AF:

0.646

Gnomad SAS

AF:

0.312

Gnomad FIN

AF:

0.307

Gnomad MID

AF:

0.275

Gnomad NFE

AF:

0.213

Gnomad OTH

AF:

0.263

GnomAD2 exomes

AF:

0.303

AC:

76066

AN:

251404

AF XY:

0.297

show subpopulations

Gnomad AFR exome

AF:

0.260

Gnomad AMR exome

AF:

0.409

Gnomad ASJ exome

AF:

0.327

Gnomad EAS exome

AF:

0.651

Gnomad FIN exome

AF:

0.303

Gnomad NFE exome

AF:

0.216

Gnomad OTH exome

AF:

0.295

GnomAD4 exome

AF:

0.244

AC:

356834

AN:

1461862

Hom.:

49502

Cov.:

AF XY:

0.246

AC XY:

179247

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.261

AC:

8722

AN:

33480

American (AMR)

AF:

0.399

AC:

17860

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.326

AC:

8519

AN:

26136

East Asian (EAS)

AF:

0.673

AC:

26702

AN:

39696

South Asian (SAS)

AF:

0.314

AC:

27097

AN:

86258

European-Finnish (FIN)

AF:

0.292

AC:

15605

AN:

53418

Middle Eastern (MID)

AF:

0.276

AC:

1592

AN:

5768

European-Non Finnish (NFE)

AF:

0.211

AC:

234413

AN:

1111990

Other (OTH)

AF:

0.270

AC:

16324

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

17630

35260

52889

70519

88149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8442

16884

25326

33768

42210

<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:

0.265

AC:

40263

AN:

152034

Hom.:

5975

Cov.:

AF XY:

0.273

AC XY:

20268

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.255

AC:

10576

AN:

41486

American (AMR)

AF:

0.331

AC:

5060

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.337

AC:

1171

AN:

3472

East Asian (EAS)

AF:

0.645

AC:

3319

AN:

5144

South Asian (SAS)

AF:

0.314

AC:

1514

AN:

4824

European-Finnish (FIN)

AF:

0.307

AC:

3243

AN:

10564

Middle Eastern (MID)

AF:

0.269

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.213

AC:

14484

AN:

67966

Other (OTH)

AF:

0.270

AC:

570

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1443

2886

4329

5772

7215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

410

820

1230

1640

2050

<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:

0.233

Hom.:

11145

Bravo

AF:

0.272

Asia WGS

AF:

0.449

AC:

1558

AN:

3478

EpiCase

AF:

0.226

EpiControl

AF:

0.220

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Long QT syndrome (3)

not provided (3)

Long QT syndrome 2 (2)

Cardiac arrhythmia (1)

Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

1.9

(source)

DANN

Benign

0.88

PhyloP100

-0.95

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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