19-50320289-A-G

Variant names:

• chr19-50320289-A-G
• NM_004977.3:c.2231T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004977.3(KCNC3):​c.2231T>C​(p.Leu744Ser) variant causes a missense 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 16)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNC3 NM_004977.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.462
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21747905).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNC3	NM_004977.3	c.2231T>C	p.Leu744Ser	missense_variant	Exon 4 of 5	ENST00000477616.2	NP_004968.2
KCNC3	NM_001372305.1	c.2003T>C	p.Leu668Ser	missense_variant	Exon 4 of 5		NP_001359234.1
KCNC3	NR_110912.2	n.260+304T>C		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNC3	ENST00000477616.2	c.2231T>C	p.Leu744Ser	missense_variant	Exon 4 of 5	1	NM_004977.3	ENSP00000434241.1
KCNC3	ENST00000670667.1	c.2170+304T>C		intron_variant	Intron 3 of 3			ENSP00000499301.1
KCNC3	ENST00000376959.6	c.2170+304T>C		intron_variant	Intron 3 of 4	5		ENSP00000366158.2
KCNC3	ENST00000474951.1	c.118+304T>C		intron_variant	Intron 2 of 3	2		ENSP00000432438.1

Frequencies

GnomAD3 genomes Cov.: 16

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 793994 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 383866

African (AFR) AF: 0.00 AC: 0 AN: 18702

American (AMR) AF: 0.00 AC: 0 AN: 12752

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11286

East Asian (EAS) AF: 0.00 AC: 0 AN: 19328

South Asian (SAS) AF: 0.00 AC: 0 AN: 39014

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2560

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 636286

Other (OTH) AF: 0.00 AC: 0 AN: 32270

GnomAD4 genome Cov.: 16

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spinocerebellar ataxia type 13 Uncertain:1

Aug 15, 2024

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PM2 supporting, BP4 supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.37	T
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	-0.0070	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.46
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.69	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.057	T
Polyphen		0.81	P
Vest4		0.32
MutPred		0.13		Gain of glycosylation at L744 (P = 0.0049);
MVP		0.64
ClinPred		0.26	T
GERP RS		1.2
Varity_R		0.095
gMVP		0.30
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

hg19: chr19-50823546;