chr19-50320324-G-A

Variant names:

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

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>T​(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 Benign (★). Synonymous variant affecting the same amino acid position (i.e. P732P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 17)
  • Exomes 𝑓: 0.00072 (2 hom.)
• Consequence: KCNC3 NM_004977.3 synonymous
• Clinical Significance: 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=-0.5).
• BP6: Variant 19-50320324-G-A is Benign according to our data. Variant chr19-50320324-G-A is described in ClinVar as [Benign]. Clinvar id is 2650318.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 afr. GnomAd4 allele frequency = 0.00305 (396/129712) while in subpopulation AFR AF = 0.0104 (364/34952). AF 95% confidence interval is 0.00953. There are 1 homozygotes in GnomAd4. There are 171 alleles in the male GnomAd4 subpopulation. Median coverage is 17. This position passed quality control check.
• BS2: High AC in GnomAd4 at 396 AD gene.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00305 AC: 395 AN: 129610 Hom.: 1 Cov.: 17

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00152

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: 0.000132

Gnomad OTH AF: 0.00224

GnomAD2 exomes AF: 0.00145 AC: 78 AN: 53844 AF XY: 0.00135

Gnomad AFR exome AF: 0.0124

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000147

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000718 AC: 218 AN: 303490 Hom.: 2 Cov.: 4 AF XY: 0.000603 AC XY: 95 AN XY: 157512

African (AFR) AF: 0.0179 AC: 158 AN: 8840

American (AMR) AF: 0.00155 AC: 20 AN: 12878

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 14820

South Asian (SAS) AF: 0.00 AC: 0 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: 0.0000693 AC: 13 AN: 187662

Other (OTH) AF: 0.00169 AC: 27 AN: 16010

GnomAD4 genome AF: 0.00305 AC: 396 AN: 129712 Hom.: 1 Cov.: 17 AF XY: 0.00275 AC XY: 171 AN XY: 62118

African (AFR) AF: 0.0104 AC: 364 AN: 34952

American (AMR) AF: 0.00152 AC: 20 AN: 13172

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: 0.000132 AC: 8 AN: 60470

Other (OTH) AF: 0.00221 AC: 4 AN: 1808

Alfa AF: 0.000188 Hom.: 0

Bravo AF: 0.00394

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNC3: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.4
DANN	Benign	0.74
PhyloP100		0.69
Mutation Taster		=97/3	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: rs375488867; hg19: chr19-50823581;