chr19-50323024-G-A

Variant names:

• chr19-50323024-G-A
• rs111744086
• NM_004977.3:c.1929C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004977.3(KCNC3):​c.1929C>T​(p.Gly643Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,545,834 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (26 hom., cov: 32)
  • Exomes 𝑓: 0.010 (105 hom.)
• Consequence: KCNC3 NM_004977.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.84
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 19-50323024-G-A is Benign according to our data. Variant chr19-50323024-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 288184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.84 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0142 (2155/152246) while in subpopulation AFR AF = 0.0236 (979/41564). AF 95% confidence interval is 0.0223. There are 26 homozygotes in GnomAd4. There are 1013 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2155 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.1929C>T	p.Gly643Gly	synonymous	Exon 2 of 5	NP_004968.2
	KCNC3	NM_001372305.1		c.1701C>T	p.Gly567Gly	synonymous	Exon 2 of 5	NP_001359234.1
	KCNC3	NR_110912.2		n.69-2240C>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.1929C>T	p.Gly643Gly	synonymous	Exon 2 of 5	ENSP00000434241.1	Q14003
	KCNC3	ENST00000670667.1		c.1929C>T	p.Gly643Gly	synonymous	Exon 2 of 4	ENSP00000499301.1	A0A590UJ62
	KCNC3	ENST00000376959.6	TSL:5	c.1929C>T	p.Gly643Gly	synonymous	Exon 2 of 5	ENSP00000366158.2	E7ETH1

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2150 AN: 152128 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.0235

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00566

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.00953 AC: 1358 AN: 142518 AF XY: 0.00937

Gnomad AFR exome AF: 0.0229

Gnomad AMR exome AF: 0.0113

Gnomad ASJ exome AF: 0.00838

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00860

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.0105 AC: 14593 AN: 1393588 Hom.: 105 Cov.: 33 AF XY: 0.0102 AC XY: 7002 AN XY: 687196

African (AFR) AF: 0.0230 AC: 725 AN: 31520

American (AMR) AF: 0.0108 AC: 383 AN: 35326

Ashkenazi Jewish (ASJ) AF: 0.00843 AC: 210 AN: 24922

East Asian (EAS) AF: 0.0000560 AC: 2 AN: 35738

South Asian (SAS) AF: 0.00313 AC: 246 AN: 78628

European-Finnish (FIN) AF: 0.00806 AC: 384 AN: 47626

Middle Eastern (MID) AF: 0.0102 AC: 48 AN: 4700

European-Non Finnish (NFE) AF: 0.0111 AC: 11966 AN: 1077412

Other (OTH) AF: 0.0109 AC: 629 AN: 57716

GnomAD4 genome AF: 0.0142 AC: 2155 AN: 152246 Hom.: 26 Cov.: 32 AF XY: 0.0136 AC XY: 1013 AN XY: 74452

African (AFR) AF: 0.0236 AC: 979 AN: 41564

American (AMR) AF: 0.0177 AC: 271 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4824

European-Finnish (FIN) AF: 0.00566 AC: 60 AN: 10602

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0113 AC: 771 AN: 68004

Other (OTH) AF: 0.0156 AC: 33 AN: 2114

Alfa AF: 0.0123 Hom.: 9

Bravo AF: 0.0155

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Spinocerebellar ataxia type 13 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	1.6
DANN	Benign	0.84
PhyloP100		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs111744086; hg19: chr19-50826281; COSMIC: COSV65387044;