dbSNP rs551056698: KCNH2:p.Gly187_Gly189del (chr7-150958406-GCGCCCGCGC-G) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM4BP6BS1BS2

The NM_000238.4(KCNH2):c.560_568delGCGCGGGCG(p.Gly187_Gly189del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000745 in 1,447,500 control chromosomes in the GnomAD database, including 12 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G187G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0026 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00052 ( 8 hom. )

Consequence

KCNH2
NM_000238.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:10

Conservation

PhyloP100: 2.40

Publications

3 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 -7 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000238.4.

BP6

Variant 7-150958406-GCGCCCGCGC-G is Benign according to our data. Variant chr7-150958406-GCGCCCGCGC-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 200600.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00262 (399/152010) while in subpopulation AFR AF = 0.00848 (352/41532). AF 95% confidence interval is 0.00775. There are 4 homozygotes in GnomAd4. There are 178 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 399 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.560_568delGCGCGGGCG	p.Gly187_Gly189del	disruptive_inframe_deletion	Exon 4 of 15	NP_000229.1	A0A090N8Q0
KCNH2	NM_001406753.1		c.272_280delGCGCGGGCG	p.Gly91_Gly93del	disruptive_inframe_deletion	Exon 2 of 13	NP_001393682.1	Q12809-7
KCNH2	NM_172056.3		c.560_568delGCGCGGGCG	p.Gly187_Gly189del	disruptive_inframe_deletion	Exon 4 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.560_568delGCGCGGGCG	p.Gly187_Gly189del	disruptive_inframe_deletion	Exon 4 of 15	ENSP00000262186.5	Q12809-1
KCNH2	ENST00000713710.1		c.560_568delGCGCGGGCG	p.Gly187_Gly189del	disruptive_inframe_deletion	Exon 4 of 15	ENSP00000519013.1	A0AAQ5BGR0
KCNH2	ENST00000713701.1		c.260_268delGCGCGGGCG	p.Gly87_Gly89del	disruptive_inframe_deletion	Exon 3 of 14	ENSP00000519004.1	A0AAQ5BGQ9

Frequencies

GnomAD3 genomes

AF:

0.00263

AC:

399

AN:

151902

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00850

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000525

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000772

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000339

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.000879

AC:

AN:

63692

AF XY:

0.000964

show subpopulations

Gnomad AFR exome

AF:

0.0162

Gnomad AMR exome

AF:

0.00115

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000885

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000394

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000525

AC:

680

AN:

1295490

Hom.:

AF XY:

0.000542

AC XY:

346

AN XY:

638402

show subpopulations

African (AFR)

AF:

0.00878

AC:

226

AN:

25742

American (AMR)

AF:

0.00124

AC:

AN:

20892

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21674

East Asian (EAS)

AF:

0.000429

AC:

AN:

27994

South Asian (SAS)

AF:

0.00169

AC:

116

AN:

68732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32462

Middle Eastern (MID)

AF:

0.000474

AC:

AN:

4216

European-Non Finnish (NFE)

AF:

0.000246

AC:

256

AN:

1040334

Other (OTH)

AF:

0.000786

AC:

AN:

53444

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

119

149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00262

AC:

399

AN:

152010

Hom.:

Cov.:

AF XY:

0.00239

AC XY:

178

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.00848

AC:

352

AN:

41532

American (AMR)

AF:

0.000524

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000774

AC:

AN:

5166

South Asian (SAS)

AF:

0.00166

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10510

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000339

AC:

AN:

67934

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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.:

Bravo

AF:

0.00294

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (2)

Cardiovascular phenotype (1)

Long QT syndrome (1)

Long QT syndrome 1 (1)

Long QT syndrome 2 (1)

Short QT syndrome type 1;C3150943:Long QT syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.4

Mutation Taster

=166/34

polymorphism

(source)

Splicing

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