19-18880284-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021267.5(CERS1):c.742G>A(p.Gly248Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000358 in 1,398,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

CERS1
NM_021267.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.772

Publications

0 publications found

Variant links:

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]

CERS1 links:

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)

GDF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.08621082).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CERS1	NM_021267.5 link	c.742G>A	p.Gly248Ser	missense_variant	Exon 4 of 8	ENST00000623882.4	NP_067090.1	P27544-1
GDF1	NM_001492.6 link	c.-581G>A		5_prime_UTR_variant	Exon 4 of 8	ENST00000247005.8	NP_001483.3	P27539A0A024R7N8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CERS1	ENST00000623882.4 link	c.742G>A	p.Gly248Ser	missense_variant	Exon 4 of 8	1	NM_021267.5	ENSP00000485308.1		P27544-1
GDF1	ENST00000247005.8 link	c.-581G>A		5_prime_UTR_variant	Exon 4 of 8	1	NM_001492.6	ENSP00000247005.5		P27539

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000358

AC:

AN:

1398082

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

689622

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31604

American (AMR)

AF:

0.00

AC:

AN:

35750

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25096

East Asian (EAS)

AF:

0.00

AC:

AN:

35806

South Asian (SAS)

AF:

0.00

AC:

AN:

79056

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4638

European-Non Finnish (NFE)

AF:

0.00000463

AC:

AN:

1079028

Other (OTH)

AF:

0.00

AC:

AN:

57942

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Progressive myoclonic epilepsy type 8

Uncertain:1

Aug 28, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine with serine at codon 248 of the CERS1 protein (p.Gly248Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with CERS1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.020

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.50

D;.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.79

T;T;T

M_CAP

Benign

0.068

MetaRNN

Benign

0.086

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.70

N;N;.

PhyloP100

0.77

PrimateAI

Benign

0.43

PROVEAN

Benign

0.95

.;N;N

REVEL

Benign

0.24

Sift

Benign

0.67

.;T;T

Sift4G

Benign

0.74

T;T;T

Polyphen

0.0020

B;.;.

Vest4

0.36

MutPred

0.51

Gain of MoRF binding (P = 0.1099);Gain of MoRF binding (P = 0.1099);.;

MVP

0.28

ClinPred

0.10

GERP RS

-7.7

Varity_R

0.019

Mutation Taster

=85/15

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over