NM_012139.4:c.1048+25529T>G

Variant names:

• chr11-17852679-A-C
• rs2023902
• NM_012139.4:c.1048+25529T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012139.4(SERGEF):​c.1048+25529T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 152,272 control chromosomes in the GnomAD database, including 2,341 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.16 (2341 hom., cov: 32)
• Consequence: SERGEF NM_012139.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.24
• Publications: 5 publications found

Genes affected

SERGEF (HGNC:17499): (secretion regulating guanine nucleotide exchange factor) Predicted to enable guanyl-nucleotide exchange factor activity. Involved in negative regulation of protein secretion. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

LOC107984317 (HGNC:):

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERGEF	NM_012139.4	c.1048+25529T>G		intron_variant	Intron 10 of 10	ENST00000265965.10	NP_036271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERGEF	ENST00000265965.10	c.1048+25529T>G		intron_variant	Intron 10 of 10	1	NM_012139.4	ENSP00000265965.5

Frequencies

GnomAD3 genomes AF: 0.165 AC: 25033 AN: 152152 Hom.: 2343 Cov.: 32

Gnomad AFR AF: 0.0861

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.283

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.187

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.164 AC: 25024 AN: 152272 Hom.: 2341 Cov.: 32 AF XY: 0.163 AC XY: 12124 AN XY: 74456

African (AFR) AF: 0.0860 AC: 3575 AN: 41562

American (AMR) AF: 0.141 AC: 2160 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 983 AN: 3468

East Asian (EAS) AF: 0.111 AC: 575 AN: 5178

South Asian (SAS) AF: 0.190 AC: 914 AN: 4822

European-Finnish (FIN) AF: 0.172 AC: 1824 AN: 10622

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.212 AC: 14423 AN: 67996

Other (OTH) AF: 0.185 AC: 391 AN: 2116

Alfa AF: 0.197 Hom.: 2249

Bravo AF: 0.157

Asia WGS AF: 0.152 AC: 530 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.7
DANN	Benign	0.71
PhyloP100		3.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs2023902; hg19: chr11-17874226;