dbSNP rs144926928: KCNH2:p.Pro440Pro (chr7-150952662-C-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_000238.4(KCNH2):c.1320G>T(p.Pro440Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000287 in 1,614,166 control chromosomes in the GnomAD database, including 9 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. P440P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00031 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 7 hom. )

Consequence

KCNH2
NM_000238.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:9

Conservation

PhyloP100: -0.796

Publications

4 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: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 7-150952662-C-A is Benign according to our data. Variant chr7-150952662-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215441.

BP7

Synonymous conserved (PhyloP=-0.796 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000285 (417/1461886) while in subpopulation MID AF = 0.016 (92/5768). AF 95% confidence interval is 0.0133. There are 7 homozygotes in GnomAdExome4. There are 227 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAd4 at 47 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	UniProt
KCNH2	NM_000238.4	MANE Select	c.1320G>T	p.Pro440Pro	synonymous	Exon 6 of 15	NP_000229.1	A0A090N8Q0
KCNH2	NM_001406753.1		c.1032G>T	p.Pro344Pro	synonymous	Exon 4 of 13	NP_001393682.1	Q12809-7
KCNH2	NM_172056.3		c.1320G>T	p.Pro440Pro	synonymous	Exon 6 of 9	NP_742053.1	Q12809-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.1320G>T	p.Pro440Pro	synonymous	Exon 6 of 15	ENSP00000262186.5	Q12809-1
KCNH2	ENST00000330883.9	TSL:1	c.300G>T	p.Pro100Pro	synonymous	Exon 2 of 11	ENSP00000328531.4	Q12809-2
KCNH2	ENST00000461280.2	TSL:1	n.618G>T		non_coding_transcript_exon	Exon 2 of 5

Frequencies

GnomAD3 genomes

AF:

0.000315

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000346

AC:

AN:

251476

AF XY:

0.000390

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000510

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000285

AC:

417

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000312

AC XY:

227

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000313

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.0160

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000210

AC:

234

AN:

1112010

Other (OTH)

AF:

0.000629

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

130

162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000309

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41560

American (AMR)

AF:

0.000523

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000828

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

68018

Other (OTH)

AF:

0.00236

AC:

AN:

2116

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:

0.000285

Hom.:

Bravo

AF:

0.000295

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000711

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Long QT syndrome (2)

Cardiac arrhythmia (1)

Cardiovascular phenotype (1)

Long QT syndrome 2 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.88

(source)

DANN

Benign

0.52

PhyloP100

-0.80

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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.

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