11-17736591-A-T

Variant names:

• chr11-17736591-A-T
• rs186151622
• NM_001112741.2:c.570+19A>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• progressive myoclonic epilepsy type 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
• progressive myoclonus epilepsy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 425 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001112741.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNC1	NM_001112741.2	MANE Select	c.570+19A>T		intron	N/A	NP_001106212.1
	KCNC1	NM_004976.4		c.570+19A>T		intron	N/A	NP_004967.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNC1	ENST00000265969.8	TSL:5 MANE Select	c.570+19A>T		intron	N/A	ENSP00000265969.7
	KCNC1	ENST00000379472.4	TSL:1	c.570+19A>T		intron	N/A	ENSP00000368785.3
	KCNC1	ENST00000639325.2	TSL:5	c.570+19A>T		intron	N/A	ENSP00000492663.2

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

GnomAD2 exomes AF: 0.00295 AC: 273 AN: 92534 AF XY: 0.00324

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 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

African (AFR) AF: 0.000713 AC: 21 AN: 29434

American (AMR) AF: 0.00262 AC: 70 AN: 26708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21320

East Asian (EAS) AF: 0.00 AC: 0 AN: 35952

South Asian (SAS) AF: 0.00402 AC: 281 AN: 69978

European-Finnish (FIN) AF: 0.000621 AC: 20 AN: 32196

Middle Eastern (MID) AF: 0.000378 AC: 2 AN: 5294

European-Non Finnish (NFE) AF: 0.00484 AC: 5115 AN: 1056994

Other (OTH) AF: 0.00271 AC: 150 AN: 55370

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

African (AFR) AF: 0.000865 AC: 36 AN: 41598

American (AMR) AF: 0.00399 AC: 61 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00331 AC: 16 AN: 4828

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00435 AC: 296 AN: 68022

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00284 Hom.: 1

Bravo AF: 0.00282

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Progressive myoclonic epilepsy type 7 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	4.2
DANN	Benign	0.83
PhyloP100		-0.18
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs186151622; hg19: chr11-17758138;