19-18895895-G-C

Variant names:

• chr19-18895895-G-C
• rs760185006
• NM_021267.5:c.178C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021267.5(CERS1):​c.178C>G​(p.Leu60Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000316 in 1,264,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L60L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: CERS1 NM_021267.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.855
• Publications: 0 publications found

Genes affected

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]

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]

GDF1 Gene-Disease associations (from GenCC):

• right atrial isomerism

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• congenital heart defects, multiple types, 6

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Illumina, Ambry Genetics
• conotruncal heart malformations

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12267077).

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
	CERS1	NM_021267.5	MANE Select	c.178C>G	p.Leu60Val	missense	Exon 1 of 8	NP_067090.1	P27544-1
	GDF1	NM_001492.6	MANE Select	c.-1145C>G		5_prime_UTR	Exon 1 of 8	NP_001483.3
	CERS1	NM_001387439.1		c.178C>G	p.Leu60Val	missense	Exon 1 of 7	NP_001374368.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CERS1	ENST00000623882.4	TSL:1 MANE Select	c.178C>G	p.Leu60Val	missense	Exon 1 of 8	ENSP00000485308.1	P27544-1
	CERS1	ENST00000429504.6	TSL:1	c.178C>G	p.Leu60Val	missense	Exon 1 of 6	ENSP00000389044.1	P27544-2
	GDF1	ENST00000247005.8	TSL:1 MANE Select	c.-1145C>G		5_prime_UTR	Exon 1 of 8	ENSP00000247005.5	P27539

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150546 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000180 AC: 2 AN: 1113584 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 540762

African (AFR) AF: 0.00 AC: 0 AN: 21254

American (AMR) AF: 0.00 AC: 0 AN: 8642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13444

East Asian (EAS) AF: 0.00 AC: 0 AN: 23230

South Asian (SAS) AF: 0.00 AC: 0 AN: 40308

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2836

European-Non Finnish (NFE) AF: 0.00000213 AC: 2 AN: 937426

Other (OTH) AF: 0.00 AC: 0 AN: 43184

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150546 Hom.: 0 Cov.: 30 AF XY: 0.0000136 AC XY: 1 AN XY: 73504

African (AFR) AF: 0.00 AC: 0 AN: 41234

American (AMR) AF: 0.000132 AC: 2 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67478

Other (OTH) AF: 0.00 AC: 0 AN: 2068

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
-	1	-	Progressive myoclonic epilepsy type 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.85
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.0070
Sift	Benign	0.27	T
Sift4G	Benign	0.45	T
Polyphen		0.036	B
Vest4		0.17
MutPred		0.42		Loss of glycosylation at P58 (P = 0.1015)
MVP		0.34
ClinPred		0.052	T
GERP RS		2.1
PromoterAI		-0.24	Neutral
Varity_R		0.11
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs760185006; hg19: chr19-19006704;