2-17919648-T-C

Variant names:

• chr2-17919648-T-C
• rs1564008
• NM_002252.5:c.-60+1777T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002252.5(KCNS3):​c.-60+1777T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.952 in 152,356 control chromosomes in the GnomAD database, including 69,087 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 0.95 (69074 hom., cov: 33)
  • Exomes 𝑓: 0.96 (13 hom.)
• Consequence: KCNS3 NM_002252.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.14
• Publications: 0 publications found

Genes affected

KCNS3 (HGNC:6302): (potassium voltage-gated channel modifier subfamily S member 3) 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. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Sep 2013]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNS3	NM_002252.5	c.-60+1777T>C		intron_variant	Intron 2 of 2	ENST00000304101.9	NP_002243.3
KCNS3	NM_001282428.2	c.-60+1777T>C		intron_variant	Intron 2 of 2		NP_001269357.1
KCNS3	XM_011532825.2	c.-431+1777T>C		intron_variant	Intron 2 of 3		XP_011531127.1
KCNS3	XM_047444255.1	c.-60+1777T>C		intron_variant	Intron 2 of 2		XP_047300211.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNS3	ENST00000304101.9	c.-60+1777T>C		intron_variant	Intron 2 of 2	1	NM_002252.5	ENSP00000305824.4

Frequencies

GnomAD3 genomes AF: 0.952 AC: 144857 AN: 152210 Hom.: 69017 Cov.: 33

Gnomad AFR AF: 0.896

Gnomad AMI AF: 0.968

Gnomad AMR AF: 0.974

Gnomad ASJ AF: 0.958

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.989

Gnomad FIN AF: 0.978

Gnomad MID AF: 0.975

Gnomad NFE AF: 0.969

Gnomad OTH AF: 0.950

GnomAD4 exome AF: 0.964 AC: 27 AN: 28 Hom.: 13 Cov.: 0 AF XY: 0.938 AC XY: 15 AN XY: 16

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 1.00 AC: 4 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.955 AC: 21 AN: 22

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.952 AC: 144972 AN: 152328 Hom.: 69074 Cov.: 33 AF XY: 0.954 AC XY: 71078 AN XY: 74486

African (AFR) AF: 0.896 AC: 37248 AN: 41554

American (AMR) AF: 0.974 AC: 14915 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.958 AC: 3326 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5180 AN: 5180

South Asian (SAS) AF: 0.989 AC: 4776 AN: 4830

European-Finnish (FIN) AF: 0.978 AC: 10395 AN: 10626

Middle Eastern (MID) AF: 0.983 AC: 289 AN: 294

European-Non Finnish (NFE) AF: 0.969 AC: 65951 AN: 68040

Other (OTH) AF: 0.950 AC: 2009 AN: 2114

Alfa AF: 0.956 Hom.: 25890

Bravo AF: 0.948

Asia WGS AF: 0.992 AC: 3449 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.99
DANN	Benign	0.44
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1564008; hg19: chr2-18100915;