20-45094928-T-C

Position:

• chr20-45094928-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001322799.2(KCNS1):​c.1523A>G​(p.Gln508Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00295 in 1,613,916 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.014 (52 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (49 hom.)
• Consequence: KCNS1 NM_001322799.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00300

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015424192).
• BP6: Variant 20-45094928-T-C is Benign according to our data. Variant chr20-45094928-T-C is described in ClinVar as [Benign]. Clinvar id is 769094.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 = 0.0144 (2190/152068) while in subpopulation AFR AF= 0.0487 (2021/41480). AF 95% confidence interval is 0.047. There are 52 homozygotes in gnomad4. There are 1011 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 52 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNS1	NM_001322799.2	c.1523A>G	p.Gln508Arg	missense_variant	4/4	ENST00000537075.3	NP_001309728.1
KCNS1	NM_002251.5	c.1523A>G	p.Gln508Arg	missense_variant	5/5		NP_002242.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNS1	ENST00000537075.3	c.1523A>G	p.Gln508Arg	missense_variant	4/4	1	NM_001322799.2	ENSP00000445595.1
KCNS1	ENST00000306117.5	c.1523A>G	p.Gln508Arg	missense_variant	5/5	1		ENSP00000307694.1

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2183 AN: 151950 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.0487

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00622

Gnomad ASJ AF: 0.00376

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00312

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00440 AC: 1106 AN: 251368 Hom.: 27 AF XY: 0.00353 AC XY: 480 AN XY: 135854

Gnomad AFR exome AF: 0.0500

Gnomad AMR exome AF: 0.00315

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00265

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000369

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00176 AC: 2579 AN: 1461848 Hom.: 49 Cov.: 30 AF XY: 0.00159 AC XY: 1158 AN XY: 727228

Gnomad4 AFR exome AF: 0.0479

Gnomad4 AMR exome AF: 0.00362

Gnomad4 ASJ exome AF: 0.00413

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00188

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000215

Gnomad4 OTH exome AF: 0.00475

GnomAD4 genome AF: 0.0144 AC: 2190 AN: 152068 Hom.: 52 Cov.: 32 AF XY: 0.0136 AC XY: 1011 AN XY: 74338

Gnomad4 AFR AF: 0.0487

Gnomad4 AMR AF: 0.00628

Gnomad4 ASJ AF: 0.00376

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00313

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00326 Hom.: 18

Bravo AF: 0.0164

ESP6500AA AF: 0.0522 AC: 230

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00538 AC: 653

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 21, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.50
DANN	Benign	0.22
DEOGEN2	Benign	0.052	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0036	N
LIST_S2	Benign	0.12	.;T
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	-0.46	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.010	N;N
REVEL	Benign	0.26
Sift	Benign	0.68	T;T
Sift4G	Benign	0.62	T;T
Polyphen		0.0	B;B
Vest4		0.014
MVP		0.60
ClinPred		0.00030	T
GERP RS		0.93
Varity_R		0.034
gMVP		0.21

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

LitVar

Other links and lift over

dbSNP: rs7264544; hg19: chr20-43723569;