rs734784

Positions:

• chr20-45094986-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001322799.2(KCNS1):​c.1465A>G​(p.Ile489Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.44 in 1,613,382 control chromosomes in the GnomAD database, including 160,825 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.47 (17379 hom., cov: 29)
  • Exomes 𝑓: 0.44 (143446 hom.)
• Consequence: KCNS1 NM_001322799.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.514

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.79946E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNS1	NM_001322799.2	c.1465A>G	p.Ile489Val	missense_variant	4/4	ENST00000537075.3
KCNS1	NM_002251.5	c.1465A>G	p.Ile489Val	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNS1	ENST00000537075.3	c.1465A>G	p.Ile489Val	missense_variant	4/4	1	NM_001322799.2	P1
KCNS1	ENST00000306117.5	c.1465A>G	p.Ile489Val	missense_variant	5/5	1		P1

Frequencies

GnomAD3 genomes AF: 0.470 AC: 71250 AN: 151550 Hom.: 17340 Cov.: 29

Gnomad AFR AF: 0.563

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.415

Gnomad ASJ AF: 0.400

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.488

GnomAD3 exomes AF: 0.409 AC: 102918 AN: 251364 Hom.: 22515 AF XY: 0.408 AC XY: 55480 AN XY: 135850

Gnomad AFR exome AF: 0.565

Gnomad AMR exome AF: 0.314

Gnomad ASJ exome AF: 0.404

Gnomad EAS exome AF: 0.196

Gnomad SAS exome AF: 0.305

Gnomad FIN exome AF: 0.525

Gnomad NFE exome AF: 0.457

Gnomad OTH exome AF: 0.422

GnomAD4 exome AF: 0.437 AC: 638464 AN: 1461714 Hom.: 143446 Cov.: 56 AF XY: 0.433 AC XY: 315022 AN XY: 727162

Gnomad4 AFR exome AF: 0.558

Gnomad4 AMR exome AF: 0.328

Gnomad4 ASJ exome AF: 0.411

Gnomad4 EAS exome AF: 0.159

Gnomad4 SAS exome AF: 0.306

Gnomad4 FIN exome AF: 0.517

Gnomad4 NFE exome AF: 0.454

Gnomad4 OTH exome AF: 0.439

GnomAD4 genome AF: 0.470 AC: 71344 AN: 151668 Hom.: 17379 Cov.: 29 AF XY: 0.470 AC XY: 34782 AN XY: 74072

Gnomad4 AFR AF: 0.564

Gnomad4 AMR AF: 0.415

Gnomad4 ASJ AF: 0.400

Gnomad4 EAS AF: 0.196

Gnomad4 SAS AF: 0.292

Gnomad4 FIN AF: 0.539

Gnomad4 NFE AF: 0.451

Gnomad4 OTH AF: 0.491

Alfa AF: 0.447 Hom.: 31460

Bravo AF: 0.467

TwinsUK AF: 0.456 AC: 1692

ALSPAC AF: 0.460 AC: 1773

ESP6500AA AF: 0.565 AC: 2490

ESP6500EA AF: 0.450 AC: 3866

ExAC AF: 0.413 AC: 50106

Asia WGS AF: 0.293 AC: 1019 AN: 3478

EpiCase AF: 0.456

EpiControl AF: 0.457

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.11
DANN	Benign	0.18
DEOGEN2	Benign	0.056	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0039	N
MetaRNN	Benign	0.000018	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.46	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.14	N;N
REVEL	Benign	0.23
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.0070
ClinPred		0.0022	T
GERP RS		0.29
Varity_R		0.030
gMVP		0.23

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: rs734784; hg19: chr20-43723627; COSMIC: COSV60259341;