19-50320285-G-T

Variant names:

• chr19-50320285-G-T
• rs755400651
• NM_004977.3:c.2235C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_004977.3(KCNC3):​c.2235C>A​(p.Pro745Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P745P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 17)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: KCNC3 NM_004977.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.33
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP7: Synonymous conserved (PhyloP=1.33 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNC3	NM_004977.3	c.2235C>A	p.Pro745Pro	synonymous_variant	Exon 4 of 5	ENST00000477616.2	NP_004968.2
KCNC3	NM_001372305.1	c.2007C>A	p.Pro669Pro	synonymous_variant	Exon 4 of 5		NP_001359234.1
KCNC3	NR_110912.2	n.260+308C>A		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNC3	ENST00000477616.2	c.2235C>A	p.Pro745Pro	synonymous_variant	Exon 4 of 5	1	NM_004977.3	ENSP00000434241.1
KCNC3	ENST00000670667.1	c.2170+308C>A		intron_variant	Intron 3 of 3			ENSP00000499301.1
KCNC3	ENST00000376959.6	c.2170+308C>A		intron_variant	Intron 3 of 4	5		ENSP00000366158.2
KCNC3	ENST00000474951.1	c.118+308C>A		intron_variant	Intron 2 of 3	2		ENSP00000432438.1

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD4 exome AF: 0.00000218 AC: 2 AN: 916832 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 442886

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

African (AFR) AF: 0.00 AC: 0 AN: 21616

American (AMR) AF: 0.00 AC: 0 AN: 14526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14116

East Asian (EAS) AF: 0.0000395 AC: 1 AN: 25296

South Asian (SAS) AF: 0.00 AC: 0 AN: 39648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3202

European-Non Finnish (NFE) AF: 0.00000137 AC: 1 AN: 731518

Other (OTH) AF: 0.00 AC: 0 AN: 38436

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.006664), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 17

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Benign	0.75
PhyloP100		1.3

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

dbSNP: rs755400651; hg19: chr19-50823542;