chr12-50138603-C-G

Variant names:

• chr12-50138603-C-G
• NM_147190.5:c.507G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_147190.5(CERS5):​c.507G>C​(p.Trp169Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CERS5 NM_147190.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.83
• Publications: 0 publications found

Genes affected

CERS5 (HGNC:23749): (ceramide synthase 5) This gene encodes a protein that belongs to the TLC (TRAM, LAG1 and CLN8 homology domains) family of proteins. The encoded protein functions in the synthesis of ceramide, a lipid molecule that is involved in a several cellular signaling pathways. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ENSG00000272368 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_147190.5. 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
	CERS5	NM_147190.5	MANE Select	c.507G>C	p.Trp169Cys	missense	Exon 5 of 10	NP_671723.1	Q8N5B7-1
	CERS5	NM_001331070.3		c.507G>C	p.Trp169Cys	missense	Exon 5 of 11	NP_001317999.1
	CERS5	NM_001331071.3		c.507G>C	p.Trp169Cys	missense	Exon 5 of 11	NP_001318000.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CERS5	ENST00000317551.12	TSL:2 MANE Select	c.507G>C	p.Trp169Cys	missense	Exon 5 of 10	ENSP00000325485.6	Q8N5B7-1
	CERS5	ENST00000380189.8	TSL:1	n.449G>C		non_coding_transcript_exon	Exon 4 of 10	ENSP00000369536.4	Q49AQ3
	CERS5	ENST00000898651.1		c.594G>C	p.Trp198Cys	missense	Exon 5 of 10	ENSP00000568710.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461512 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727078

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111730

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.8
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-11	D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.92	P
Vest4		0.93
MutPred		0.63		Gain of catalytic residue at W167 (P = 0)
MVP		0.65
MPC		1.4
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.92
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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

hg19: chr12-50532386;