rs1232558368

Variant names:

• chr19-50328314-G-T
• rs1232558368
• NM_004977.3:c.769C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004977.3(KCNC3):​c.769C>A​(p.Pro257Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000417 in 1,128,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: KCNC3 NM_004977.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.50
• 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: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18358856).
• BS2: High AC in GnomAdExome4 at 46 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004977.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNC3	NM_004977.3	MANE Select	c.769C>A	p.Pro257Thr	missense	Exon 1 of 5	NP_004968.2
	KCNC3	NM_001372305.1		c.541C>A	p.Pro181Thr	missense	Exon 1 of 5	NP_001359234.1
	KCNC3	NR_110912.2		n.68+5155C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNC3	ENST00000477616.2	TSL:1 MANE Select	c.769C>A	p.Pro257Thr	missense	Exon 1 of 5	ENSP00000434241.1	Q14003
	KCNC3	ENST00000670667.1		c.769C>A	p.Pro257Thr	missense	Exon 1 of 4	ENSP00000499301.1	A0A590UJ62
	KCNC3	ENST00000376959.6	TSL:5	c.769C>A	p.Pro257Thr	missense	Exon 1 of 5	ENSP00000366158.2	E7ETH1

Frequencies

GnomAD3 genomes AF: 0.00000675 AC: 1 AN: 148060 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000469 AC: 46 AN: 980002 Hom.: 0 Cov.: 33 AF XY: 0.0000474 AC XY: 22 AN XY: 464486

African (AFR) AF: 0.00 AC: 0 AN: 19326

American (AMR) AF: 0.00 AC: 0 AN: 5506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9732

East Asian (EAS) AF: 0.00 AC: 0 AN: 15222

South Asian (SAS) AF: 0.00 AC: 0 AN: 19054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13698

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2360

European-Non Finnish (NFE) AF: 0.0000524 AC: 45 AN: 858870

Other (OTH) AF: 0.0000276 AC: 1 AN: 36234

GnomAD4 genome AF: 0.00000675 AC: 1 AN: 148060 Hom.: 0 Cov.: 30 AF XY: 0.0000139 AC XY: 1 AN XY: 72092

African (AFR) AF: 0.0000245 AC: 1 AN: 40878

American (AMR) AF: 0.00 AC: 0 AN: 14914

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3404

East Asian (EAS) AF: 0.00 AC: 0 AN: 5096

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66506

Other (OTH) AF: 0.00 AC: 0 AN: 2038

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.66	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	0.81	L
PhyloP100		1.5
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.75	N
REVEL	Uncertain	0.34
Sift	Benign	0.38	T
Sift4G	Benign	0.23	T
Polyphen		0.0060	B
Vest4		0.18
MutPred		0.25		Gain of phosphorylation at P257 (P = 0.0108)
MVP		0.75
ClinPred		0.076	T
GERP RS		0.95
Varity_R		0.13
gMVP		0.15
Mutation Taster		=93/7	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: rs1232558368; hg19: chr19-50831571;