11-17771838-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001112741.2(KCNC1):c.744C>T(p.Ile248=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.04 in 1,614,160 control chromosomes in the GnomAD database, including 1,462 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (120 hom., cov: 33)
  • Exomes 𝑓: 0.041 (1342 hom.)
• Consequence: KCNC1 NM_001112741.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.320

Genes affected

KCNC1 (HGNC:6233): (potassium voltage-gated channel subfamily C member 1) This gene encodes a member of a family of integral membrane proteins that mediate the voltage-dependent potassium ion permeability of excitable membranes. Alternative splicing is thought to result in two transcript variants encoding isoforms that differ at their C-termini. These isoforms have had conflicting names in the literature: the longer isoform has been called both "b" and "alpha", while the shorter isoform has been called both "a" and "beta" (PMIDs 1432046, 12091563). [provided by RefSeq, Oct 2014]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 11-17771838-C-T is Benign according to our data. Variant chr11-17771838-C-T is described in ClinVar as [Benign]. Clinvar id is 475360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.32 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.062 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNC1	NM_001112741.2	c.744C>T	p.Ile248=	synonymous_variant	2/4	ENST00000265969.8
KCNC1	NM_004976.4	c.744C>T	p.Ile248=	synonymous_variant	2/2
KCNC1	XM_047426916.1	c.744C>T	p.Ile248=	synonymous_variant	2/4
KCNC1	XR_930866.3	n.1966C>T		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNC1	ENST00000265969.8	c.744C>T	p.Ile248=	synonymous_variant	2/4	5	NM_001112741.2	P1

Frequencies

GnomAD3 genomes AF: 0.0312 AC: 4746 AN: 152208 Hom.: 120 Cov.: 33

Gnomad AFR AF: 0.00745

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0651

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00931

Gnomad FIN AF: 0.0335

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0426

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.0306 AC: 7698 AN: 251482 Hom.: 175 AF XY: 0.0290 AC XY: 3941 AN XY: 135912

Gnomad AFR exome AF: 0.00732

Gnomad AMR exome AF: 0.0457

Gnomad ASJ exome AF: 0.0194

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.0103

Gnomad FIN exome AF: 0.0287

Gnomad NFE exome AF: 0.0410

Gnomad OTH exome AF: 0.0311

GnomAD4 exome AF: 0.0410 AC: 59892 AN: 1461834 Hom.: 1342 Cov.: 32 AF XY: 0.0400 AC XY: 29100 AN XY: 727204

Gnomad4 AFR exome AF: 0.00639

Gnomad4 AMR exome AF: 0.0478

Gnomad4 ASJ exome AF: 0.0199

Gnomad4 EAS exome AF: 0.000705

Gnomad4 SAS exome AF: 0.0113

Gnomad4 FIN exome AF: 0.0306

Gnomad4 NFE exome AF: 0.0472

Gnomad4 OTH exome AF: 0.0310

GnomAD4 genome AF: 0.0312 AC: 4751 AN: 152326 Hom.: 120 Cov.: 33 AF XY: 0.0316 AC XY: 2355 AN XY: 74498

Gnomad4 AFR AF: 0.00743

Gnomad4 AMR AF: 0.0653

Gnomad4 ASJ AF: 0.0176

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00952

Gnomad4 FIN AF: 0.0335

Gnomad4 NFE AF: 0.0426

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0322 Hom.: 42

Bravo AF: 0.0319

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.0375

EpiControl AF: 0.0362

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 25, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

KCNC1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Progressive myoclonic epilepsy type 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	6.8
Dann	Benign	0.87

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

Publications

LitVar

Other links and lift over

dbSNP: rs2229007; hg19: chr11-17793385; COSMIC: COSV56395531; COSMIC: COSV56395531;