chr19-50320357-T-G

Position:

• chr19-50320357-T-G

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
KCNC3	NM_004977.3	c.2171-8A>C		splice_region_variant, intron_variant		ENST00000477616.2	NP_004968.2
KCNC3	NM_001372305.1	c.1943-8A>C		splice_region_variant, intron_variant			NP_001359234.1
KCNC3	NR_110912.2	n.260+236A>C		intron_variant

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00 AC: 132 AN: 21994 Hom.: 0 Cov.: 0 FAILED QC

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

GnomAD3 exomes AF: 0.00637 AC: 255 AN: 40016 Hom.: 0 AF XY: 0.00748 AC XY: 152 AN XY: 20320

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 SAS exome AF: 0.00122

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

Gnomad4 AFR exome AF: 0.000767

Gnomad4 AMR exome AF: 0.000337

Gnomad4 ASJ exome AF: 0.000256

Gnomad4 EAS exome AF: 0.000130

Gnomad4 SAS exome AF: 0.000191

Gnomad4 FIN exome AF: 0.00543

Gnomad4 NFE exome AF: 0.000653

Gnomad4 OTH exome AF: 0.00113

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

Gnomad4 AFR AF: 0.00213

Gnomad4 AMR AF: 0.00757

Gnomad4 ASJ AF: 0.00299

Gnomad4 EAS AF: 0.00329

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00363

Gnomad4 NFE AF: 0.00841

Gnomad4 OTH AF: 0.0112

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	KCNC3: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2021	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

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

Publications

LitVar

Other links and lift over

dbSNP: rs775357041; hg19: chr19-50823614; COSMIC: COSV65386698;