rs1365532889

Variant names:

• chr19-50320275-C-A
• rs1365532889
• NM_004977.3:c.2245G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-50320275-C-A
• chr19-50320275-C-T

Variant summary

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

The NM_004977.3(KCNC3):​c.2245G>T​(p.Ala749Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A749T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 16)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: KCNC3 NM_004977.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.92
• Publications: 0 publications found

Genes affected

KCNC3 (HGNC:6235): (potassium voltage-gated channel subfamily C member 3) The Shaker gene family of Drosophila encodes components of voltage-gated potassium channels and is comprised of four subfamilies. Based on sequence similarity, this gene is similar to one of these subfamilies, namely the Shaw subfamily. The protein encoded by this gene belongs to the delayed rectifier class of channel proteins and is an integral membrane protein that mediates the voltage-dependent potassium ion permeability of excitable membranes. Alternate splicing results in several transcript variants. [provided by RefSeq, Mar 2014]

KCNC3 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia type 13

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.25802088).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNC3	NM_004977.3	c.2245G>T	p.Ala749Ser	missense_variant	Exon 4 of 5	ENST00000477616.2	NP_004968.2
KCNC3	NM_001372305.1	c.2017G>T	p.Ala673Ser	missense_variant	Exon 4 of 5		NP_001359234.1
KCNC3	NR_110912.2	n.260+318G>T		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNC3	ENST00000477616.2	c.2245G>T	p.Ala749Ser	missense_variant	Exon 4 of 5	1	NM_004977.3	ENSP00000434241.1
KCNC3	ENST00000670667.1	c.2170+318G>T		intron_variant	Intron 3 of 3			ENSP00000499301.1
KCNC3	ENST00000376959.6	c.2170+318G>T		intron_variant	Intron 3 of 4	5		ENSP00000366158.2
KCNC3	ENST00000474951.1	c.118+318G>T		intron_variant	Intron 2 of 3	2		ENSP00000432438.1

Frequencies

GnomAD3 genomes Cov.: 16

GnomAD4 exome AF: 0.00000109 AC: 1 AN: 916720 Hom.: 0 Cov.: 13 AF XY: 0.00000225 AC XY: 1 AN XY: 444652

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

African (AFR) AF: 0.00 AC: 0 AN: 21636

American (AMR) AF: 0.00 AC: 0 AN: 15058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14720

East Asian (EAS) AF: 0.00 AC: 0 AN: 28858

South Asian (SAS) AF: 0.00 AC: 0 AN: 37340

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3094

European-Non Finnish (NFE) AF: 0.00000138 AC: 1 AN: 724786

Other (OTH) AF: 0.00 AC: 0 AN: 39240

⚠️ 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 Cov.: 16

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.087	T
Eigen	Benign	-0.012
Eigen_PC	Benign	-0.011
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	0.46	D
MutationAssessor	Benign	0.0	N
PhyloP100		2.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.26	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.016	D
Sift4G	Benign	0.45	T
Polyphen		0.82	P
Vest4		0.24
MutPred		0.090		Gain of glycosylation at A749 (P = 0.0087);
MVP		0.75
ClinPred		0.48	T
GERP RS		2.3
Varity_R		0.13
gMVP		0.14
Mutation Taster		=97/3	polymorphism

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: rs1365532889; hg19: chr19-50823532;