19-50320375-A-G

Variant names:

• chr19-50320375-A-G
• rs185032351
• NM_004977.3:c.2171-26T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004977.3(KCNC3):​c.2171-26T>C variant causes a intron 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (69 hom., cov: 12)
  • Exomes 𝑓: 0.019 (60 hom.)
• Consequence: KCNC3 NM_004977.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.908
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 19-50320375-A-G is Benign according to our data. Variant chr19-50320375-A-G is described in ClinVar as [Benign]. Clinvar id is 1257797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNC3	NM_004977.3	c.2171-26T>C		intron_variant	Intron 3 of 4	ENST00000477616.2	NP_004968.2
KCNC3	NM_001372305.1	c.1943-26T>C		intron_variant	Intron 3 of 4		NP_001359234.1
KCNC3	NR_110912.2	n.260+218T>C		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNC3	ENST00000477616.2	c.2171-26T>C		intron_variant	Intron 3 of 4	1	NM_004977.3	ENSP00000434241.1
KCNC3	ENST00000670667.1	c.2170+218T>C		intron_variant	Intron 3 of 3			ENSP00000499301.1
KCNC3	ENST00000376959.6	c.2170+218T>C		intron_variant	Intron 3 of 4	5		ENSP00000366158.2
KCNC3	ENST00000474951.1	c.118+218T>C		intron_variant	Intron 2 of 3	2		ENSP00000432438.1

Frequencies

GnomAD3 genomes AF: 0.0486 AC: 3001 AN: 61686 Hom.: 69 Cov.: 12

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0630

Gnomad ASJ AF: 0.00936

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00919

Gnomad FIN AF: 0.0158

Gnomad MID AF: 0.0667

Gnomad NFE AF: 0.0201

Gnomad OTH AF: 0.0572

GnomAD2 exomes AF: 0.0157 AC: 860 AN: 54766 AF XY: 0.0147

Gnomad AFR exome AF: 0.0722

Gnomad AMR exome AF: 0.0182

Gnomad ASJ exome AF: 0.00671

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00558

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.0120

GnomAD4 exome AF: 0.0190 AC: 5004 AN: 262846 Hom.: 60 Cov.: 4 AF XY: 0.0172 AC XY: 2402 AN XY: 139886

African (AFR) AF: 0.101 AC: 818 AN: 8096

American (AMR) AF: 0.0225 AC: 303 AN: 13442

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 90 AN: 7078

East Asian (EAS) AF: 0.000144 AC: 2 AN: 13886

South Asian (SAS) AF: 0.00361 AC: 148 AN: 40994

European-Finnish (FIN) AF: 0.0145 AC: 200 AN: 13822

Middle Eastern (MID) AF: 0.0188 AC: 32 AN: 1700

European-Non Finnish (NFE) AF: 0.0204 AC: 3051 AN: 149524

Other (OTH) AF: 0.0252 AC: 360 AN: 14304

GnomAD4 genome AF: 0.0487 AC: 3006 AN: 61706 Hom.: 69 Cov.: 12 AF XY: 0.0513 AC XY: 1435 AN XY: 27976

African (AFR) AF: 0.120 AC: 1964 AN: 16418

American (AMR) AF: 0.0629 AC: 280 AN: 4452

Ashkenazi Jewish (ASJ) AF: 0.00936 AC: 17 AN: 1816

East Asian (EAS) AF: 0.00 AC: 0 AN: 1890

South Asian (SAS) AF: 0.00921 AC: 15 AN: 1628

European-Finnish (FIN) AF: 0.0158 AC: 38 AN: 2400

Middle Eastern (MID) AF: 0.0698 AC: 6 AN: 86

European-Non Finnish (NFE) AF: 0.0201 AC: 639 AN: 31780

Other (OTH) AF: 0.0566 AC: 47 AN: 830

Alfa AF: 0.0321 Hom.: 59

Bravo AF: 0.0299

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	13
DANN	Benign	0.64
PhyloP100		0.91
Mutation Taster		=99/1	polymorphism (auto)

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: rs185032351; hg19: chr19-50823632;