chr19-50320323-G-A

Variant names:

• chr19-50320323-G-A
• rs756181510
• NM_004977.3:c.2197C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 8P and 8B. PVS1 BS1 BS2

The NM_004977.3(KCNC3):​c.2197C>T​(p.Gln733*) variant causes a stop gained change. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000077 (0 hom., cov: 17)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: KCNC3 NM_004977.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.76
• Publications: 1 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, MODERATE, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000144 (5/346118) while in subpopulation AFR AF = 0.000311 (3/9640). AF 95% confidence interval is 0.000084. There are 0 homozygotes in GnomAdExome4. There are 1 alleles in the male GnomAdExome4 subpopulation. Median coverage is 6. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 5 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.2197C>T	p.Gln733*	stop_gained	Exon 4 of 5	NP_004968.2
	KCNC3	NM_001372305.1		c.1969C>T	p.Gln657*	stop_gained	Exon 4 of 5	NP_001359234.1
	KCNC3	NR_110912.2		n.260+270C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNC3	ENST00000477616.2	TSL:1 MANE Select	c.2197C>T	p.Gln733*	stop_gained	Exon 4 of 5	ENSP00000434241.1	Q14003
	KCNC3	ENST00000670667.1		c.2170+270C>T		intron	N/A	ENSP00000499301.1	A0A590UJ62
	KCNC3	ENST00000376959.6	TSL:5	c.2170+270C>T		intron	N/A	ENSP00000366158.2	E7ETH1

Frequencies

GnomAD3 genomes AF: 0.00000769 AC: 1 AN: 130110 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.0000286

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

GnomAD2 exomes AF: 0.0000184 AC: 1 AN: 54204 AF XY: 0.00

Gnomad AFR exome AF: 0.000190

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 5 AN: 346118 Hom.: 0 Cov.: 6 AF XY: 0.00000563 AC XY: 1 AN XY: 177576

African (AFR) AF: 0.000311 AC: 3 AN: 9640

American (AMR) AF: 0.00 AC: 0 AN: 12974

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8230

East Asian (EAS) AF: 0.00 AC: 0 AN: 15446

South Asian (SAS) AF: 0.00 AC: 0 AN: 37838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1712

European-Non Finnish (NFE) AF: 0.00000885 AC: 2 AN: 225910

Other (OTH) AF: 0.00 AC: 0 AN: 17326

GnomAD4 genome AF: 0.00000769 AC: 1 AN: 130110 Hom.: 0 Cov.: 17 AF XY: 0.0000161 AC XY: 1 AN XY: 62304

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

African (AFR) AF: 0.0000286 AC: 1 AN: 34978

American (AMR) AF: 0.00 AC: 0 AN: 13282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3176

East Asian (EAS) AF: 0.00 AC: 0 AN: 3618

South Asian (SAS) AF: 0.00 AC: 0 AN: 3356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 60692

Other (OTH) AF: 0.00 AC: 0 AN: 1788

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.82	D
PhyloP100		3.8
Vest4		0.50
GERP RS		2.3
Mutation Taster		=68/132	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs756181510; hg19: chr19-50823580;