19-50320276-G-A

Variant names:

• chr19-50320276-G-A
• rs1027819501
• NM_004977.3:c.2244C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_004977.3(KCNC3):​c.2244C>T​(p.Asn748Asn) 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000029 (0 hom., cov: 17)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: KCNC3 NM_004977.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.734
• 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 19-50320276-G-A is Benign according to our data. Variant chr19-50320276-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 916248.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.734 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNC3	NM_004977.3	c.2244C>T	p.Asn748Asn	synonymous_variant	Exon 4 of 5	ENST00000477616.2	NP_004968.2
KCNC3	NM_001372305.1	c.2016C>T	p.Asn672Asn	synonymous_variant	Exon 4 of 5		NP_001359234.1
KCNC3	NR_110912.2	n.260+317C>T		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNC3	ENST00000477616.2	c.2244C>T	p.Asn748Asn	synonymous_variant	Exon 4 of 5	1	NM_004977.3	ENSP00000434241.1
KCNC3	ENST00000670667.1	c.2170+317C>T		intron_variant	Intron 3 of 3			ENSP00000499301.1
KCNC3	ENST00000376959.6	c.2170+317C>T		intron_variant	Intron 3 of 4	5		ENSP00000366158.2
KCNC3	ENST00000474951.1	c.118+317C>T		intron_variant	Intron 2 of 3	2		ENSP00000432438.1

Frequencies

GnomAD3 genomes AF: 0.0000291 AC: 4 AN: 137660 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.0000273

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: 0.000111

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000314

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000687 AC: 4 AN: 58218 AF XY: 0.0000660

Gnomad AFR exome AF: 0.000182

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000284

Gnomad NFE exome AF: 0.0000439

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000245 AC: 23 AN: 937992 Hom.: 0 Cov.: 13 AF XY: 0.0000264 AC XY: 12 AN XY: 453804

African (AFR) AF: 0.00 AC: 0 AN: 22112

American (AMR) AF: 0.00 AC: 0 AN: 14890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14640

East Asian (EAS) AF: 0.00 AC: 0 AN: 27362

South Asian (SAS) AF: 0.0000258 AC: 1 AN: 38696

European-Finnish (FIN) AF: 0.000129 AC: 4 AN: 31036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3286

European-Non Finnish (NFE) AF: 0.0000228 AC: 17 AN: 746274

Other (OTH) AF: 0.0000252 AC: 1 AN: 39696

GnomAD4 genome AF: 0.0000290 AC: 4 AN: 137780 Hom.: 0 Cov.: 17 AF XY: 0.0000300 AC XY: 2 AN XY: 66720

African (AFR) AF: 0.0000273 AC: 1 AN: 36690

American (AMR) AF: 0.00 AC: 0 AN: 13900

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3324

East Asian (EAS) AF: 0.00 AC: 0 AN: 4312

South Asian (SAS) AF: 0.00 AC: 0 AN: 3912

European-Finnish (FIN) AF: 0.000111 AC: 1 AN: 9036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.0000314 AC: 2 AN: 63600

Other (OTH) AF: 0.00 AC: 0 AN: 1892

Alfa AF: 0.000122 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 01, 2020

CeGaT Center for Human Genetics Tuebingen

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	-0.49
CADD	Benign	15
DANN	Benign	0.87
PhyloP100		0.73

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: rs1027819501; hg19: chr19-50823533; COSMIC: COSV100979415;