chr12-50134563-C-A

Variant names:

• chr12-50134563-C-A
• rs776527448
• NM_147190.5:c.1012G>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_147190.5(CERS5):​c.1012G>T​(p.Ala338Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,614,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: CERS5 NM_147190.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79
• 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.39509186).

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.1012G>T	p.Ala338Ser	missense	Exon 9 of 10	NP_671723.1	Q8N5B7-1
	CERS5	NM_001331070.3		c.1012G>T	p.Ala338Ser	missense	Exon 9 of 11	NP_001317999.1
	CERS5	NM_001331071.3		c.1012G>T	p.Ala338Ser	missense	Exon 9 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.1012G>T	p.Ala338Ser	missense	Exon 9 of 10	ENSP00000325485.6	Q8N5B7-1
	CERS5	ENST00000380189.8	TSL:1	n.*366G>T		non_coding_transcript_exon	Exon 8 of 10	ENSP00000369536.4	Q49AQ3
	CERS5	ENST00000548942.1	TSL:1	n.245G>T		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152166 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251422 AF XY: 0.0000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000499 AC: 73 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.0000646 AC XY: 47 AN XY: 727246

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0000396 AC: 44 AN: 1112006

Other (OTH) AF: 0.0000993 AC: 6 AN: 60396

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152284 Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3 AN XY: 74440

African (AFR) AF: 0.00 AC: 0 AN: 41546

American (AMR) AF: 0.000131 AC: 2 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.0000806 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000494 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

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	Benign	0.19
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.18
Sift	Benign	0.30	T
Sift4G	Benign	0.57	T
Polyphen		0.13	B
Vest4		0.64
MutPred		0.45		Gain of catalytic residue at L339 (P = 0.0017)
MVP		0.44
MPC		0.37
ClinPred		0.26	T
GERP RS		5.0
Varity_R		0.29
gMVP		0.62
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs776527448; hg19: chr12-50528346;