11-17736591-A-T

Position:

• chr11-17736591-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001112741.2(KCNC1):​c.570+19A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0041 in 1,485,572 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (24 hom.)
• Consequence: KCNC1 NM_001112741.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.177

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]

KCNC1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 11-17736591-A-T is Benign according to our data. Variant chr11-17736591-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 445584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00279 (425/152326) while in subpopulation NFE AF= 0.00435 (296/68022). AF 95% confidence interval is 0.00394. There are 4 homozygotes in gnomad4. There are 213 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 425 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNC1	NM_001112741.2	c.570+19A>T		intron_variant		ENST00000265969.8	NP_001106212.1
KCNC1	NM_004976.4	c.570+19A>T		intron_variant			NP_004967.1
KCNC1	XM_047426916.1	c.570+19A>T		intron_variant			XP_047282872.1
KCNC1	XR_930866.3	n.1792+19A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNC1	ENST00000265969.8	c.570+19A>T		intron_variant		5	NM_001112741.2	ENSP00000265969.7

Frequencies

GnomAD3 genomes AF: 0.00279 AC: 424 AN: 152208 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00434

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00295 AC: 273 AN: 92534 Hom.: 3 AF XY: 0.00324 AC XY: 165 AN XY: 50864

Gnomad AFR exome AF: 0.00139

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00347

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00409

Gnomad OTH exome AF: 0.00535

GnomAD4 exome AF: 0.00424 AC: 5659 AN: 1333246 Hom.: 24 Cov.: 32 AF XY: 0.00419 AC XY: 2737 AN XY: 653466

Gnomad4 AFR exome AF: 0.000713

Gnomad4 AMR exome AF: 0.00262

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00402

Gnomad4 FIN exome AF: 0.000621

Gnomad4 NFE exome AF: 0.00484

Gnomad4 OTH exome AF: 0.00271

GnomAD4 genome AF: 0.00279 AC: 425 AN: 152326 Hom.: 4 Cov.: 32 AF XY: 0.00286 AC XY: 213 AN XY: 74490

Gnomad4 AFR AF: 0.000865

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00435

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00284 Hom.: 1

Bravo AF: 0.00282

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Progressive myoclonic epilepsy type 7 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 14, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 08, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	4.2
DANN	Benign	0.83

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: rs186151622; hg19: chr11-17758138;