20-45094880-T-G

Position:

• chr20-45094880-T-G

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.1571A>C​(p.Gln524Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,611,390 control chromosomes in the GnomAD database, including 60 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0099 (20 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (40 hom.)
• Consequence: KCNS1 NM_001322799.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.754

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=0.0032248795).
• BP6: Variant 20-45094880-T-G is Benign according to our data. Variant chr20-45094880-T-G is described in ClinVar as [Benign]. Clinvar id is 779990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00989 (1504/152102) while in subpopulation EAS AF= 0.0351 (181/5164). AF 95% confidence interval is 0.0309. There are 20 homozygotes in gnomad4. There are 707 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNS1	NM_001322799.2	c.1571A>C	p.Gln524Pro	missense_variant	4/4	ENST00000537075.3
KCNS1	NM_002251.5	c.1571A>C	p.Gln524Pro	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNS1	ENST00000537075.3	c.1571A>C	p.Gln524Pro	missense_variant	4/4	1	NM_001322799.2	P1
KCNS1	ENST00000306117.5	c.1571A>C	p.Gln524Pro	missense_variant	5/5	1		P1

Frequencies

GnomAD3 genomes AF: 0.00981 AC: 1491 AN: 151984 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0300

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0350

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00505 AC: 1258 AN: 249296 Hom.: 15 AF XY: 0.00420 AC XY: 566 AN XY: 134742

Gnomad AFR exome AF: 0.0309

Gnomad AMR exome AF: 0.00137

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0323

Gnomad SAS exome AF: 0.00286

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.00263

GnomAD4 exome AF: 0.00193 AC: 2817 AN: 1459288 Hom.: 40 Cov.: 29 AF XY: 0.00187 AC XY: 1355 AN XY: 725854

Gnomad4 AFR exome AF: 0.0300

Gnomad4 AMR exome AF: 0.00177

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0304

Gnomad4 SAS exome AF: 0.00251

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.00420

GnomAD4 genome AF: 0.00989 AC: 1504 AN: 152102 Hom.: 20 Cov.: 32 AF XY: 0.00951 AC XY: 707 AN XY: 74364

Gnomad4 AFR AF: 0.0300

Gnomad4 AMR AF: 0.00223

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0351

Gnomad4 SAS AF: 0.00229

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00460 Hom.: 4

Bravo AF: 0.0107

ESP6500AA AF: 0.0268 AC: 118

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00540 AC: 656

Asia WGS AF: 0.0250 AC: 88 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 28, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	14
DANN	Benign	0.79
DEOGEN2	Benign	0.095	T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.40	.;T
MetaRNN	Benign	0.0032	T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	0.81	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0050	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.072	B;B
Vest4		0.26
MVP		0.82
ClinPred		0.017	T
GERP RS		3.0
Varity_R		0.15
gMVP		0.39

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: rs61731056; hg19: chr20-43723521; COSMIC: COSV60259335;