Genetic Variant KCNS1:p.Glu86Glu (chr20-45098514-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BA1

The NM_001322799.2(KCNS1):c.258G>A(p.Glu86Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,519,866 control chromosomes in the GnomAD database, including 50,129 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.20 ( 3807 hom., cov: 32)

Exomes 𝑓: 0.25 ( 46322 hom. )

Consequence

KCNS1
NM_001322799.2 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.39

Publications

15 publications found

Variant links:

Genes affected

KCNS1 (HGNC:6300): (potassium voltage-gated channel modifier subfamily S member 1) Voltage-gated potassium channels form the largest and most diversified class of ion channels and are present in both excitable and nonexcitable cells. Their main functions are associated with the regulation of the resting membrane potential and the control of the shape and frequency of action potentials. The alpha subunits are of 2 types: those that are functional by themselves and those that are electrically silent but capable of modulating the activity of specific functional alpha subunits. The protein encoded by this gene is not functional by itself but can form heteromultimers with member 1 and with member 2 (and possibly other members) of the Shab-related subfamily of potassium voltage-gated channel proteins. This gene belongs to the S subfamily of the potassium channel family. [provided by RefSeq, Jul 2008]

KCNS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP7

Synonymous conserved (PhyloP=2.39 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNS1	NM_001322799.2 link	c.258G>A	p.Glu86Glu	synonymous_variant	Exon 3 of 4	ENST00000537075.3	NP_001309728.1	Q96KK3A2RUL8
KCNS1	NM_002251.5 link	c.258G>A	p.Glu86Glu	synonymous_variant	Exon 4 of 5		NP_002242.2	Q96KK3A2RUL8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNS1	ENST00000537075.3 link	c.258G>A	p.Glu86Glu	synonymous_variant	Exon 3 of 4	1	NM_001322799.2	ENSP00000445595.1		Q96KK3
KCNS1	ENST00000306117.5 link	c.258G>A	p.Glu86Glu	synonymous_variant	Exon 4 of 5	1		ENSP00000307694.1		Q96KK3

Frequencies

GnomAD3 genomes

AF:

0.198

AC:

29984

AN:

151316

Hom.:

3807

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0503

Gnomad AMI

AF:

0.204

Gnomad AMR

AF:

0.197

Gnomad ASJ

AF:

0.226

Gnomad EAS

AF:

0.110

Gnomad SAS

AF:

0.116

Gnomad FIN

AF:

0.364

Gnomad MID

AF:

0.360

Gnomad NFE

AF:

0.273

Gnomad OTH

AF:

0.218

GnomAD2 exomes

AF:

0.224

AC:

26741

AN:

119644

AF XY:

0.221

show subpopulations

Gnomad AFR exome

AF:

0.0518

Gnomad AMR exome

AF:

0.159

Gnomad ASJ exome

AF:

0.228

Gnomad EAS exome

AF:

0.123

Gnomad FIN exome

AF:

0.347

Gnomad NFE exome

AF:

0.286

Gnomad OTH exome

AF:

0.248

GnomAD4 exome

AF:

0.253

AC:

345675

AN:

1368440

Hom.:

46322

Cov.:

AF XY:

0.250

AC XY:

168828

AN XY:

674488

show subpopulations

African (AFR)

AF:

0.0465

AC:

1320

AN:

28394

American (AMR)

AF:

0.161

AC:

5379

AN:

33350

Ashkenazi Jewish (ASJ)

AF:

0.233

AC:

5669

AN:

24284

East Asian (EAS)

AF:

0.0877

AC:

2836

AN:

32320

South Asian (SAS)

AF:

0.121

AC:

9176

AN:

76060

European-Finnish (FIN)

AF:

0.345

AC:

16286

AN:

47248

Middle Eastern (MID)

AF:

0.269

AC:

1249

AN:

4650

European-Non Finnish (NFE)

AF:

0.272

AC:

290134

AN:

1065540

Other (OTH)

AF:

0.241

AC:

13626

AN:

56594

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

15288

30577

45865

61154

76442

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9642

19284

28926

38568

48210

<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:

0.198

AC:

29974

AN:

151426

Hom.:

3807

Cov.:

AF XY:

0.201

AC XY:

14914

AN XY:

74036

show subpopulations

African (AFR)

AF:

0.0501

AC:

2073

AN:

41394

American (AMR)

AF:

0.197

AC:

2991

AN:

15212

Ashkenazi Jewish (ASJ)

AF:

0.226

AC:

784

AN:

3462

East Asian (EAS)

AF:

0.108

AC:

553

AN:

5106

South Asian (SAS)

AF:

0.117

AC:

561

AN:

4814

European-Finnish (FIN)

AF:

0.364

AC:

3776

AN:

10378

Middle Eastern (MID)

AF:

0.353

AC:

103

AN:

292

European-Non Finnish (NFE)

AF:

0.273

AC:

18489

AN:

67766

Other (OTH)

AF:

0.219

AC:

460

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1171

2342

3514

4685

5856

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

318

636

954

1272

1590

<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:

0.244

Hom.:

1463

Bravo

AF:

0.182

Asia WGS

AF:

0.133

AC:

462

AN:

3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

0.97

PhyloP100

2.4

Mutation Taster

=98/2

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over