Genetic Variant NM_001322799.2:c.1121G>A (chr20-45095330-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001322799.2(KCNS1):c.1121G>A(p.Arg374His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,612,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

KCNS1
NM_001322799.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.74

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22428596).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001322799.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNS1	NM_001322799.2	MANE Select	c.1121G>A	p.Arg374His	missense	Exon 4 of 4	NP_001309728.1	Q96KK3
	KCNS1	NM_002251.5		c.1121G>A	p.Arg374His	missense	Exon 5 of 5	NP_002242.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNS1	ENST00000537075.3	TSL:1 MANE Select	c.1121G>A	p.Arg374His	missense	Exon 4 of 4	ENSP00000445595.1	Q96KK3
	KCNS1	ENST00000306117.5	TSL:1	c.1121G>A	p.Arg374His	missense	Exon 5 of 5	ENSP00000307694.1	Q96KK3

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000443

AC:

AN:

248516

AF XY:

0.0000446

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000535

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000112

AC:

164

AN:

1459832

Hom.:

Cov.:

AF XY:

0.000114

AC XY:

AN XY:

726094

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26002

East Asian (EAS)

AF:

0.000202

AC:

AN:

39664

South Asian (SAS)

AF:

0.000313

AC:

AN:

86144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52872

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000109

AC:

121

AN:

1110934

Other (OTH)

AF:

0.0000829

AC:

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41534

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000831

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

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:

0.0000963

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000577

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000594

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.050

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

Eigen

Benign

-0.011

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.042

MetaRNN

Benign

0.22

MetaSVM

Uncertain

0.50

MutationAssessor

Benign

0.95

PhyloP100

2.7

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.62

REVEL

Uncertain

0.38

Sift

Benign

0.33

Sift4G

Benign

0.28

Polyphen

0.15

Vest4

0.42

MVP

0.95

ClinPred

0.15

GERP RS

5.8

Varity_R

0.16

gMVP

0.85

Mutation Taster

=64/36

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