19-50320277-T-A

Variant names:

• chr19-50320277-T-A
• rs1299925483
• NM_004977.3:c.2243A>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_004977.3(KCNC3):​c.2243A>T​(p.Asn748Ile) 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 (★). Synonymous variant affecting the same amino acid position (i.e. N748N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000084 (0 hom., 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: 0.369
• 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 -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30704093).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNC3	NM_004977.3	c.2243A>T	p.Asn748Ile	missense_variant	Exon 4 of 5	ENST00000477616.2	NP_004968.2
KCNC3	NM_001372305.1	c.2015A>T	p.Asn672Ile	missense_variant	Exon 4 of 5		NP_001359234.1
KCNC3	NR_110912.2	n.260+316A>T		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNC3	ENST00000477616.2	c.2243A>T	p.Asn748Ile	missense_variant	Exon 4 of 5	1	NM_004977.3	ENSP00000434241.1
KCNC3	ENST00000670667.1	c.2170+316A>T		intron_variant	Intron 3 of 3			ENSP00000499301.1
KCNC3	ENST00000376959.6	c.2170+316A>T		intron_variant	Intron 3 of 4	5		ENSP00000366158.2
KCNC3	ENST00000474951.1	c.118+316A>T		intron_variant	Intron 2 of 3	2		ENSP00000432438.1

Frequencies

GnomAD3 genomes AF: 0.00000841 AC: 1 AN: 118920 Hom.: 0 Cov.: 16

Gnomad AFR AF: 0.00

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: 0.000159

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 819586 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 395086

African (AFR) AF: 0.00 AC: 0 AN: 18850

American (AMR) AF: 0.00 AC: 0 AN: 12124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11062

East Asian (EAS) AF: 0.00 AC: 0 AN: 20390

South Asian (SAS) AF: 0.00 AC: 0 AN: 34752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23862

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2680

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 663154

Other (OTH) AF: 0.00 AC: 0 AN: 32712

GnomAD4 genome AF: 0.00000841 AC: 1 AN: 118920 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 56114

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30954

American (AMR) AF: 0.00 AC: 0 AN: 10604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3114

East Asian (EAS) AF: 0.00 AC: 0 AN: 3404

South Asian (SAS) AF: 0.00 AC: 0 AN: 2998

European-Finnish (FIN) AF: 0.000159 AC: 1 AN: 6272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 232

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 58926

Other (OTH) AF: 0.00 AC: 0 AN: 1640

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2243A>T (p.N748I) alteration is located in exon 4 (coding exon 4) of the KCNC3 gene. This alteration results from a A to T substitution at nucleotide position 2243, causing the asparagine (N) at amino acid position 748 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.095
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	0.0	N
PhyloP100		0.37
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.50	N
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.011	D
Polyphen		0.94	P
Vest4		0.35
MutPred		0.16		Loss of loop (P = 0.0153);
MVP		0.67
ClinPred		0.58	D
GERP RS		2.2
Varity_R		0.23
gMVP		0.34
Mutation Taster		=92/8	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: rs1299925483; hg19: chr19-50823534;