Genetic Variant KCNH2:c.*15G>A (chr7-150945350-C-T) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_000238.4(KCNH2):c.*15G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,582,518 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 33 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 34 hom. )

Consequence

KCNH2
NM_000238.4 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.822

Publications

0 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 7-150945350-C-T is Benign according to our data. Variant chr7-150945350-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 359300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0114 (1735/152284) while in subpopulation AFR AF = 0.0395 (1640/41564). AF 95% confidence interval is 0.0379. There are 33 homozygotes in GnomAd4. There are 820 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1735 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	Effect	Exon Rank	Protein	UniProt
KCNH2	NM_000238.4	MANE Select	c.*15G>A	3_prime_UTR	Exon 15 of 15	NP_000229.1	A0A090N8Q0
KCNH2	NM_001406753.1		c.*15G>A	3_prime_UTR	Exon 13 of 13	NP_001393682.1	Q12809-7
KCNH2	NM_172057.3		c.*15G>A	3_prime_UTR	Exon 11 of 11	NP_742054.1	Q12809-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.*15G>A	3_prime_UTR	Exon 15 of 15	ENSP00000262186.5	Q12809-1
KCNH2	ENST00000330883.9	TSL:1	c.*15G>A	3_prime_UTR	Exon 11 of 11	ENSP00000328531.4	Q12809-2
KCNH2	ENST00000713710.1		c.*15G>A	3_prime_UTR	Exon 15 of 15	ENSP00000519013.1	A0AAQ5BGR0

Frequencies

GnomAD3 genomes

AF:

0.0114

AC:

1736

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0396

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00425

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00955

GnomAD2 exomes

AF:

0.00262

AC:

522

AN:

199372

AF XY:

0.00195

show subpopulations

Gnomad AFR exome

AF:

0.0404

Gnomad AMR exome

AF:

0.00205

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000117

Gnomad OTH exome

AF:

0.000390

GnomAD4 exome

AF:

0.00112

AC:

1597

AN:

1430234

Hom.:

Cov.:

AF XY:

0.000949

AC XY:

672

AN XY:

708458

show subpopulations

African (AFR)

AF:

0.0404

AC:

1322

AN:

32740

American (AMR)

AF:

0.00200

AC:

AN:

41092

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25578

East Asian (EAS)

AF:

0.00

AC:

AN:

37964

South Asian (SAS)

AF:

0.0000856

AC:

AN:

81776

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49918

Middle Eastern (MID)

AF:

0.00155

AC:

AN:

4526

European-Non Finnish (NFE)

AF:

0.0000419

AC:

AN:

1097602

Other (OTH)

AF:

0.00225

AC:

133

AN:

59038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

155

233

310

388

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<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:

0.0114

AC:

1735

AN:

152284

Hom.:

Cov.:

AF XY:

0.0110

AC XY:

820

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0395

AC:

1640

AN:

41564

American (AMR)

AF:

0.00425

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68006

Other (OTH)

AF:

0.00945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

161

241

322

402

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00589

Hom.:

Bravo

AF:

0.0126

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

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

-0.39

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

0.82

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

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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