19-18879243-G-C

Variant names:

• chr19-18879243-G-C
• rs373928623
• NM_001492.6:c.-425C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021267.5(CERS1):​c.898C>G​(p.Leu300Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000411 in 1,461,400 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L300L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CERS1 NM_021267.5 missense, splice_region
• Scores: Splicing: ADA: 0.008312
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.67
• Publications: 0 publications found

Genes affected

GDF1 (HGNC:4214): (growth differentiation factor 1) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. Studies in rodents suggest that this protein is involved in the establishment of left-right asymmetry in early embryogenesis and in neural development in later embryogenesis. The encoded protein is translated from a bicistronic mRNA that also encodes ceramide synthase 1. Mutations in this gene are associated with several congenital cardiovascular malformations. [provided by RefSeq, Jul 2016]

CERS1 (HGNC:14253): (ceramide synthase 1) This gene encodes a ceramide synthase enzyme, which catalyzes the synthesis of ceramide, the hydrophobic moiety of sphingolipids. The encoded enzyme synthesizes 18-carbon (C18) ceramide in brain neurons. Elevated expression of this gene may be associated with increased longevity, while decreased expression of this gene may be associated with myoclonus epilepsy with dementia in human patients. This protein is transcribed from a monocistronic mRNA as well as a bicistronic mRNA, which also encodes growth differentiation factor 1. [provided by RefSeq, Jul 2016]

CERS1 Gene-Disease associations (from GenCC):

• progressive myoclonic epilepsy type 8

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

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021267.5. 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
	GDF1	NM_001492.6	MANE Select	c.-425C>G		splice_region	Exon 5 of 8	NP_001483.3
	CERS1	NM_021267.5	MANE Select	c.898C>G	p.Leu300Val	missense splice_region	Exon 5 of 8	NP_067090.1	P27544-1
	GDF1	NM_001492.6	MANE Select	c.-425C>G		5_prime_UTR	Exon 5 of 8	NP_001483.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF1	ENST00000247005.8	TSL:1 MANE Select	c.-425C>G		splice_region	Exon 5 of 8	ENSP00000247005.5	P27539
	CERS1	ENST00000623882.4	TSL:1 MANE Select	c.898C>G	p.Leu300Val	missense splice_region	Exon 5 of 8	ENSP00000485308.1	P27544-1
	CERS1	ENST00000429504.6	TSL:1	c.898C>G	p.Leu300Val	missense splice_region	Exon 5 of 6	ENSP00000389044.1	P27544-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461400 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726968

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111786

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Benign	0.91
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.029
Eigen_PC	Benign	0.028
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.65	N
PhyloP100		3.7
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.97	N
REVEL	Uncertain	0.36
Sift	Benign	0.58	T
Sift4G	Benign	0.34	T
Polyphen		0.72	P
Vest4		0.59
MutPred		0.63		Gain of catalytic residue at L300 (P = 0.1315)
MVP		0.67
ClinPred		0.42	T
GERP RS		3.3
Varity_R		0.14
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0083
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.18		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: rs373928623; hg19: chr19-18990052;