dbSNP rs1137617: KCNH2:p.Tyr652Tyr (chr7-150951110-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000238.4(KCNH2):c.1956T>C(p.Tyr652Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.637 in 1,608,930 control chromosomes in the GnomAD database, including 331,619 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.70 ( 38734 hom., cov: 34)

Exomes 𝑓: 0.63 ( 292885 hom. )

Consequence

KCNH2
NM_000238.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: -0.277

Publications

40 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 7-150951110-A-G is Benign according to our data. Variant chr7-150951110-A-G is described in ClinVar as Benign. ClinVar VariationId is 200230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.277 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.878 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	UniProt
KCNH2	NM_000238.4	MANE Select	c.1956T>C	p.Tyr652Tyr	synonymous	Exon 8 of 15	NP_000229.1	A0A090N8Q0
KCNH2	NM_001406753.1		c.1668T>C	p.Tyr556Tyr	synonymous	Exon 6 of 13	NP_001393682.1	Q12809-7
KCNH2	NM_172056.3		c.1956T>C	p.Tyr652Tyr	synonymous	Exon 8 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.1956T>C	p.Tyr652Tyr	synonymous	Exon 8 of 15	ENSP00000262186.5	Q12809-1
KCNH2	ENST00000330883.9	TSL:1	c.936T>C	p.Tyr312Tyr	synonymous	Exon 4 of 11	ENSP00000328531.4	Q12809-2
KCNH2	ENST00000461280.2	TSL:1	n.1254T>C		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes

AF:

0.701

AC:

106660

AN:

152070

Hom.:

38677

Cov.:

show subpopulations

Gnomad AFR

AF:

0.886

Gnomad AMI

AF:

0.620

Gnomad AMR

AF:

0.654

Gnomad ASJ

AF:

0.618

Gnomad EAS

AF:

0.898

Gnomad SAS

AF:

0.669

Gnomad FIN

AF:

0.637

Gnomad MID

AF:

0.630

Gnomad NFE

AF:

0.604

Gnomad OTH

AF:

0.674

GnomAD2 exomes

AF:

0.663

AC:

164327

AN:

247964

AF XY:

0.658

show subpopulations

Gnomad AFR exome

AF:

0.898

Gnomad AMR exome

AF:

0.649

Gnomad ASJ exome

AF:

0.608

Gnomad EAS exome

AF:

0.907

Gnomad FIN exome

AF:

0.633

Gnomad NFE exome

AF:

0.603

Gnomad OTH exome

AF:

0.646

GnomAD4 exome

AF:

0.630

AC:

917867

AN:

1456742

Hom.:

292885

Cov.:

AF XY:

0.631

AC XY:

456738

AN XY:

724184

show subpopulations

African (AFR)

AF:

0.901

AC:

30118

AN:

33436

American (AMR)

AF:

0.648

AC:

28940

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.608

AC:

15827

AN:

26036

East Asian (EAS)

AF:

0.910

AC:

36066

AN:

39626

South Asian (SAS)

AF:

0.671

AC:

57752

AN:

86114

European-Finnish (FIN)

AF:

0.627

AC:

32132

AN:

51278

Middle Eastern (MID)

AF:

0.644

AC:

3708

AN:

5758

European-Non Finnish (NFE)

AF:

0.608

AC:

674213

AN:

1109566

Other (OTH)

AF:

0.649

AC:

39111

AN:

60258

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

18187

36374

54562

72749

90936

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18446

36892

55338

73784

92230

<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:

0.702

AC:

106780

AN:

152188

Hom.:

38734

Cov.:

AF XY:

0.704

AC XY:

52384

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.886

AC:

36799

AN:

41534

American (AMR)

AF:

0.654

AC:

10004

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.618

AC:

2143

AN:

3470

East Asian (EAS)

AF:

0.898

AC:

4638

AN:

5166

South Asian (SAS)

AF:

0.669

AC:

3226

AN:

4822

European-Finnish (FIN)

AF:

0.637

AC:

6740

AN:

10588

Middle Eastern (MID)

AF:

0.626

AC:

184

AN:

294

European-Non Finnish (NFE)

AF:

0.604

AC:

41046

AN:

67986

Other (OTH)

AF:

0.679

AC:

1435

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1586

3173

4759

6346

7932

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

814

1628

2442

3256

4070

<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:

0.644

Hom.:

25954

Bravo

AF:

0.712

Asia WGS

AF:

0.763

AC:

2653

AN:

3478

EpiCase

AF:

0.611

EpiControl

AF:

0.604

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (9)

not provided (3)

Long QT syndrome (2)

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

-0.72

CADD

Benign

1.2

(source)

DANN

Benign

0.50

PhyloP100

-0.28

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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