NM_004977.3:c.315G>C

Variant names:

• chr19-50328768-C-G
• rs368049323
• NM_004977.3:c.315G>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004977.3(KCNC3):​c.315G>C​(p.Thr105Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,584,580 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: KCNC3 NM_004977.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.20
• 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 19-50328768-C-G is Benign according to our data. Variant chr19-50328768-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 447624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.2 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00101 (153/151678) while in subpopulation NFE AF = 0.00164 (111/67834). AF 95% confidence interval is 0.00139. There are 0 homozygotes in GnomAd4. There are 77 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 153 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.315G>C	p.Thr105Thr	synonymous	Exon 1 of 5	NP_004968.2
	KCNC3	NM_001372305.1		c.87G>C	p.Thr29Thr	synonymous	Exon 1 of 5	NP_001359234.1
	KCNC3	NR_110912.2		n.68+4701G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNC3	ENST00000477616.2	TSL:1 MANE Select	c.315G>C	p.Thr105Thr	synonymous	Exon 1 of 5	ENSP00000434241.1	Q14003
	KCNC3	ENST00000670667.1		c.315G>C	p.Thr105Thr	synonymous	Exon 1 of 4	ENSP00000499301.1	A0A590UJ62
	KCNC3	ENST00000376959.6	TSL:5	c.315G>C	p.Thr105Thr	synonymous	Exon 1 of 5	ENSP00000366158.2	E7ETH1

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 153 AN: 151568 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000192

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00164

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00117 AC: 229 AN: 195024 AF XY: 0.00125

Gnomad AFR exome AF: 0.000666

Gnomad AMR exome AF: 0.00105

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000127

Gnomad NFE exome AF: 0.00207

Gnomad OTH exome AF: 0.00158

GnomAD4 exome AF: 0.00134 AC: 1927 AN: 1432902 Hom.: 0 Cov.: 34 AF XY: 0.00128 AC XY: 908 AN XY: 710684

African (AFR) AF: 0.000334 AC: 11 AN: 32894

American (AMR) AF: 0.000910 AC: 38 AN: 41740

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25598

East Asian (EAS) AF: 0.00 AC: 0 AN: 38294

South Asian (SAS) AF: 0.000300 AC: 25 AN: 83468

European-Finnish (FIN) AF: 0.000377 AC: 18 AN: 47736

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5192

European-Non Finnish (NFE) AF: 0.00161 AC: 1774 AN: 1098802

Other (OTH) AF: 0.00103 AC: 61 AN: 59178

GnomAD4 genome AF: 0.00101 AC: 153 AN: 151678 Hom.: 0 Cov.: 31 AF XY: 0.00104 AC XY: 77 AN XY: 74110

African (AFR) AF: 0.000338 AC: 14 AN: 41460

American (AMR) AF: 0.00137 AC: 21 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5090

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.000192 AC: 2 AN: 10418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00164 AC: 111 AN: 67834

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.000939 Hom.: 0

Bravo AF: 0.000941

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Spinocerebellar ataxia type 13 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Benign	0.93
PhyloP100		1.2
PromoterAI		0.041	Neutral
Mutation Taster		=100/0	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: rs368049323; hg19: chr19-50832025;