chr19-50320324-G-C

Variant names:

• chr19-50320324-G-C
• rs375488867
• NM_004977.3:c.2196C>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_004977.3(KCNC3):​c.2196C>G​(p.Pro732Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P732P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 17)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: KCNC3 NM_004977.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.692
• 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: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 19-50320324-G-C is Benign according to our data. Variant chr19-50320324-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 740658.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.692 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000362 (47/129718) while in subpopulation AMR AF = 0.00326 (43/13174). AF 95% confidence interval is 0.00249. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 17. This position passed quality control check.
• BS2: High AC in GnomAd4 at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNC3	NM_004977.3	c.2196C>G	p.Pro732Pro	synonymous_variant	Exon 4 of 5	ENST00000477616.2	NP_004968.2
KCNC3	NM_001372305.1	c.1968C>G	p.Pro656Pro	synonymous_variant	Exon 4 of 5		NP_001359234.1
KCNC3	NR_110912.2	n.260+269C>G		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNC3	ENST00000477616.2	c.2196C>G	p.Pro732Pro	synonymous_variant	Exon 4 of 5	1	NM_004977.3	ENSP00000434241.1
KCNC3	ENST00000670667.1	c.2170+269C>G		intron_variant	Intron 3 of 3			ENSP00000499301.1
KCNC3	ENST00000376959.6	c.2170+269C>G		intron_variant	Intron 3 of 4	5		ENSP00000366158.2
KCNC3	ENST00000474951.1	c.118+269C>G		intron_variant	Intron 2 of 3	2		ENSP00000432438.1

Frequencies

GnomAD3 genomes AF: 0.000363 AC: 47 AN: 129616 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.0000573

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

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: 0.00112

GnomAD2 exomes AF: 0.000130 AC: 7 AN: 53844 AF XY: 0.000109

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000213

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000275

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000490

Gnomad OTH exome AF: 0.00113

GnomAD4 exome AF: 0.000165 AC: 50 AN: 303490 Hom.: 0 Cov.: 4 AF XY: 0.000140 AC XY: 22 AN XY: 157512

African (AFR) AF: 0.00 AC: 0 AN: 8840

American (AMR) AF: 0.00179 AC: 23 AN: 12878

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7832

East Asian (EAS) AF: 0.000202 AC: 3 AN: 14820

South Asian (SAS) AF: 0.0000268 AC: 1 AN: 37340

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1650

European-Non Finnish (NFE) AF: 0.0000320 AC: 6 AN: 187662

Other (OTH) AF: 0.00106 AC: 17 AN: 16010

GnomAD4 genome AF: 0.000362 AC: 47 AN: 129718 Hom.: 0 Cov.: 17 AF XY: 0.000306 AC XY: 19 AN XY: 62122

African (AFR) AF: 0.0000572 AC: 2 AN: 34956

American (AMR) AF: 0.00326 AC: 43 AN: 13174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3172

East Asian (EAS) AF: 0.00 AC: 0 AN: 3590

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8134

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 258

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 60470

Other (OTH) AF: 0.00111 AC: 2 AN: 1808

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.9
DANN	Benign	0.76
PhyloP100		0.69

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: rs375488867; hg19: chr19-50823581;