19-50320323-G-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_004977.3(KCNC3):​c.2197C>A​(p.Gln733Lys) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 17)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: KCNC3 NM_004977.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.116850734).
• BP6: Variant 19-50320323-G-T is Benign according to our data. Variant chr19-50320323-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3287524.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000238 (31/130222) while in subpopulation NFE AF = 0.000363 (22/60688). AF 95% confidence interval is 0.000244. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 17. This position passed quality control check.
• BS2: High AC in GnomAd4 at 31 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>A	p.Gln733Lys	missense	Exon 4 of 5	NP_004968.2
	KCNC3	NM_001372305.1		c.1969C>A	p.Gln657Lys	missense	Exon 4 of 5	NP_001359234.1
	KCNC3	NR_110912.2		n.260+270C>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.2197C>A	p.Gln733Lys	missense	Exon 4 of 5	ENSP00000434241.1	Q14003
	KCNC3	ENST00000670667.1		c.2170+270C>A		intron	N/A	ENSP00000499301.1	A0A590UJ62
	KCNC3	ENST00000376959.6	TSL:5	c.2170+270C>A		intron	N/A	ENSP00000366158.2	E7ETH1

Frequencies

GnomAD3 genomes AF: 0.000238 AC: 31 AN: 130110 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.000200

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: 0.00345

Gnomad NFE AF: 0.000362

Gnomad OTH AF: 0.000559

GnomAD2 exomes AF: 0.0000553 AC: 3 AN: 54204 AF XY: 0.0000363

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000108

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000978

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000168 AC: 58 AN: 346114 Hom.: 0 Cov.: 6 AF XY: 0.000158 AC XY: 28 AN XY: 177572

African (AFR) AF: 0.000207 AC: 2 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: 37836

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

Middle Eastern (MID) AF: 0.000584 AC: 1 AN: 1712

European-Non Finnish (NFE) AF: 0.000226 AC: 51 AN: 225908

Other (OTH) AF: 0.000231 AC: 4 AN: 17326

GnomAD4 genome AF: 0.000238 AC: 31 AN: 130222 Hom.: 0 Cov.: 17 AF XY: 0.000272 AC XY: 17 AN XY: 62412

African (AFR) AF: 0.000200 AC: 7 AN: 35072

American (AMR) AF: 0.00 AC: 0 AN: 13300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3612

South Asian (SAS) AF: 0.00 AC: 0 AN: 3370

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

Middle Eastern (MID) AF: 0.00373 AC: 1 AN: 268

European-Non Finnish (NFE) AF: 0.000363 AC: 22 AN: 60688

Other (OTH) AF: 0.000554 AC: 1 AN: 1806

Alfa AF: 0.000279 Hom.: 0

ExAC AF: 0.0000159 AC: 1

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.34	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.21	N
REVEL	Uncertain	0.34
Sift	Benign	0.29	T
Sift4G	Benign	0.45	T
Polyphen		0.0010	B
Vest4		0.13
MVP		0.72
ClinPred		0.057	T
GERP RS		2.3
Varity_R		0.063
gMVP		0.22
Mutation Taster		=93/7	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: rs756181510; hg19: chr19-50823580;