NM_004977.3:c.23C>T

Variant names:

• chr19-50329060-G-A
• rs761806977
• NM_004977.3:c.23C>T

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.23C>T​(p.Ser8Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000114 in 1,311,576 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S8W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000029 (0 hom., cov: 22)
  • Exomes 𝑓: 0.0000094 (0 hom.)
• Consequence: KCNC3 NM_004977.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.40
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22133043).
• BS2: High AC in GnomAdExome4 at 11 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.23C>T	p.Ser8Leu	missense	Exon 1 of 5	NP_004968.2
	KCNC3	NM_001372305.1		c.-206C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	NP_001359234.1
	KCNC3	NM_001372305.1		c.-206C>T		5_prime_UTR	Exon 1 of 5	NP_001359234.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNC3	ENST00000477616.2	TSL:1 MANE Select	c.23C>T	p.Ser8Leu	missense	Exon 1 of 5	ENSP00000434241.1
	KCNC3	ENST00000670667.1		c.23C>T	p.Ser8Leu	missense	Exon 1 of 4	ENSP00000499301.1
	KCNC3	ENST00000376959.6	TSL:5	c.23C>T	p.Ser8Leu	missense	Exon 1 of 5	ENSP00000366158.2

Frequencies

GnomAD3 genomes AF: 0.0000287 AC: 4 AN: 139268 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

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: 0.000114

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000472

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000328 AC: 2 AN: 61032 AF XY: 0.0000279

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000455

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000938 AC: 11 AN: 1172308 Hom.: 0 Cov.: 20 AF XY: 0.0000104 AC XY: 6 AN XY: 574684

African (AFR) AF: 0.00 AC: 0 AN: 24398

American (AMR) AF: 0.00 AC: 0 AN: 19900

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19522

East Asian (EAS) AF: 0.00 AC: 0 AN: 25078

South Asian (SAS) AF: 0.0000394 AC: 2 AN: 50806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3242

European-Non Finnish (NFE) AF: 0.00000836 AC: 8 AN: 956984

Other (OTH) AF: 0.0000212 AC: 1 AN: 47278

GnomAD4 genome AF: 0.0000287 AC: 4 AN: 139268 Hom.: 0 Cov.: 22 AF XY: 0.0000148 AC XY: 1 AN XY: 67384

African (AFR) AF: 0.00 AC: 0 AN: 38678

American (AMR) AF: 0.00 AC: 0 AN: 13982

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3272

East Asian (EAS) AF: 0.00 AC: 0 AN: 4090

South Asian (SAS) AF: 0.00 AC: 0 AN: 3824

European-Finnish (FIN) AF: 0.000114 AC: 1 AN: 8766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000472 AC: 3 AN: 63606

Other (OTH) AF: 0.00 AC: 0 AN: 1894

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000688 AC: 1

ClinVar

ClinVar submissions as Germline

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	0.29
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	0.0	N
PhyloP100		1.4
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.34
Sift	Benign	0.20	T
Sift4G	Uncertain	0.026	D
Polyphen		0.94	P
Vest4		0.23
MutPred		0.38		Gain of sheet (P = 0.0149)
MVP		0.55
ClinPred		0.13	T
GERP RS		-0.00056
PromoterAI		-0.027	Neutral
Varity_R		0.057
gMVP		0.18
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs761806977; hg19: chr19-50832317;