NM_004977.3:c.2171-8A>C

Variant names:

• chr19-50320357-T-G
• rs775357041
• NM_004977.3:c.2171-8A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_004977.3(KCNC3):​c.2171-8A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00080 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNC3 NM_004977.3 splice_region, intron
• Scores: Splicing: ADA: 0.00005119
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.487
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 19-50320357-T-G is Benign according to our data. Variant chr19-50320357-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 1684109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNC3	NM_004977.3	c.2171-8A>C		splice_region_variant, intron_variant	Intron 3 of 4	ENST00000477616.2	NP_004968.2
KCNC3	NM_001372305.1	c.1943-8A>C		splice_region_variant, intron_variant	Intron 3 of 4		NP_001359234.1
KCNC3	NR_110912.2	n.260+236A>C		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNC3	ENST00000477616.2	c.2171-8A>C		splice_region_variant, intron_variant	Intron 3 of 4	1	NM_004977.3	ENSP00000434241.1
KCNC3	ENST00000670667.1	c.2170+236A>C		intron_variant	Intron 3 of 3			ENSP00000499301.1
KCNC3	ENST00000376959.6	c.2170+236A>C		intron_variant	Intron 3 of 4	5		ENSP00000366158.2
KCNC3	ENST00000474951.1	c.118+236A>C		intron_variant	Intron 2 of 3	2		ENSP00000432438.1

Frequencies

GnomAD3 genomes AF: 0.00600 AC: 132 AN: 21994 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00760

Gnomad ASJ AF: 0.00299

Gnomad EAS AF: 0.00330

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00363

Gnomad MID AF: 0.0333

Gnomad NFE AF: 0.00841

Gnomad OTH AF: 0.0114

GnomAD2 exomes AF: 0.00637 AC: 255 AN: 40016 AF XY: 0.00748

Gnomad AFR exome AF: 0.00165

Gnomad AMR exome AF: 0.000413

Gnomad ASJ exome AF: 0.0125

Gnomad EAS exome AF: 0.00125

Gnomad FIN exome AF: 0.0456

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.00593

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000796 AC: 122 AN: 153262 Hom.: 0 Cov.: 0 AF XY: 0.000760 AC XY: 62 AN XY: 81544

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

African (AFR) AF: 0.000767 AC: 4 AN: 5218

American (AMR) AF: 0.000337 AC: 3 AN: 8898

Ashkenazi Jewish (ASJ) AF: 0.000256 AC: 1 AN: 3910

East Asian (EAS) AF: 0.000130 AC: 1 AN: 7684

South Asian (SAS) AF: 0.000191 AC: 5 AN: 26120

European-Finnish (FIN) AF: 0.00543 AC: 39 AN: 7178

Middle Eastern (MID) AF: 0.00709 AC: 4 AN: 564

European-Non Finnish (NFE) AF: 0.000653 AC: 56 AN: 85696

Other (OTH) AF: 0.00113 AC: 9 AN: 7994

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00604 AC: 133 AN: 22018 Hom.: 0 Cov.: 0 AF XY: 0.00833 AC XY: 82 AN XY: 9844

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

African (AFR) AF: 0.00213 AC: 12 AN: 5624

American (AMR) AF: 0.00757 AC: 11 AN: 1454

Ashkenazi Jewish (ASJ) AF: 0.00299 AC: 2 AN: 670

East Asian (EAS) AF: 0.00329 AC: 2 AN: 608

South Asian (SAS) AF: 0.00 AC: 0 AN: 580

European-Finnish (FIN) AF: 0.00363 AC: 3 AN: 826

Middle Eastern (MID) AF: 0.0357 AC: 1 AN: 28

European-Non Finnish (NFE) AF: 0.00841 AC: 99 AN: 11776

Other (OTH) AF: 0.0112 AC: 3 AN: 268

⚠️ 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: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNC3: BP4, BS1 -

Nov 12, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.8
DANN	Benign	0.85
PhyloP100		0.49
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000051
dbscSNV1_RF	Benign	0.012
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: rs775357041; hg19: chr19-50823614; COSMIC: COSV65386698;