rs73424033

Variant names:

• chr11-17772330-C-T
• rs73424033
• NM_001112741.2:c.1236C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001112741.2(KCNC1):​c.1236C>T​(p.Ser412Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000551 in 1,614,176 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (4 hom.)
• Consequence: KCNC1 NM_001112741.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.112
• Publications: 3 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 11-17772330-C-T is Benign according to our data. Variant chr11-17772330-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.112 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00269 (410/152308) while in subpopulation AFR AF = 0.0095 (395/41558). AF 95% confidence interval is 0.00873. There are 1 homozygotes in GnomAd4. There are 213 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 410 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNC1	NM_001112741.2	MANE Select	c.1236C>T	p.Ser412Ser	synonymous	Exon 2 of 4	NP_001106212.1
	KCNC1	NM_004976.4		c.1236C>T	p.Ser412Ser	synonymous	Exon 2 of 2	NP_004967.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNC1	ENST00000265969.8	TSL:5 MANE Select	c.1236C>T	p.Ser412Ser	synonymous	Exon 2 of 4	ENSP00000265969.7
	KCNC1	ENST00000379472.4	TSL:1	c.1236C>T	p.Ser412Ser	synonymous	Exon 2 of 2	ENSP00000368785.3
	KCNC1	ENST00000639325.2	TSL:5	c.1236C>T	p.Ser412Ser	synonymous	Exon 2 of 5	ENSP00000492663.2

Frequencies

GnomAD3 genomes AF: 0.00267 AC: 406 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00944

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000740 AC: 186 AN: 251220 AF XY: 0.000582

Gnomad AFR exome AF: 0.00912

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000328 AC: 480 AN: 1461868 Hom.: 4 Cov.: 31 AF XY: 0.000278 AC XY: 202 AN XY: 727240

African (AFR) AF: 0.00947 AC: 317 AN: 33480

American (AMR) AF: 0.000693 AC: 31 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000737 AC: 82 AN: 1112012

Other (OTH) AF: 0.000646 AC: 39 AN: 60394

GnomAD4 genome AF: 0.00269 AC: 410 AN: 152308 Hom.: 1 Cov.: 33 AF XY: 0.00286 AC XY: 213 AN XY: 74474

African (AFR) AF: 0.00950 AC: 395 AN: 41558

American (AMR) AF: 0.000392 AC: 6 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00105 Hom.: 0

Bravo AF: 0.00277

Asia WGS AF: 0.00289 AC: 11 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Inborn genetic diseases (1)
-	-	1	KCNC1-related disorder (1)
-	-	1	Progressive myoclonic epilepsy type 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	13
DANN	Benign	0.85
PhyloP100		-0.11
PromoterAI		0.0081	Neutral
Mutation Taster		=96/4	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: rs73424033; hg19: chr11-17793877; COSMIC: COSV56395770; COSMIC: COSV56395770;