12-50144032-A-G

Position:

• chr12-50144032-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_147190.5(CERS5):​c.223T>C​(p.Cys75Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.657 in 1,608,360 control chromosomes in the GnomAD database, including 354,129 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.72 (40209 hom., cov: 32)
  • Exomes 𝑓: 0.65 (313920 hom.)
• Consequence: CERS5 NM_147190.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.541

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.035129E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.898 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CERS5	NM_147190.5	c.223T>C	p.Cys75Arg	missense_variant	2/10	ENST00000317551.12	NP_671723.1
LOC124902931	XR_007063304.1	n.492+341A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CERS5	ENST00000317551.12	c.223T>C	p.Cys75Arg	missense_variant	2/10	2	NM_147190.5	ENSP00000325485	P1
	ENST00000548468.2	n.106-20994A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.715 AC: 108723 AN: 151996 Hom.: 40155 Cov.: 32

Gnomad AFR AF: 0.883

Gnomad AMI AF: 0.552

Gnomad AMR AF: 0.714

Gnomad ASJ AF: 0.524

Gnomad EAS AF: 0.920

Gnomad SAS AF: 0.780

Gnomad FIN AF: 0.609

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.623

Gnomad OTH AF: 0.683

GnomAD3 exomes AF: 0.693 AC: 174107 AN: 251416 Hom.: 61935 AF XY: 0.688 AC XY: 93502 AN XY: 135884

Gnomad AFR exome AF: 0.887

Gnomad AMR exome AF: 0.750

Gnomad ASJ exome AF: 0.524

Gnomad EAS exome AF: 0.920

Gnomad SAS exome AF: 0.764

Gnomad FIN exome AF: 0.617

Gnomad NFE exome AF: 0.622

Gnomad OTH exome AF: 0.669

GnomAD4 exome AF: 0.651 AC: 948607 AN: 1456246 Hom.: 313920 Cov.: 32 AF XY: 0.653 AC XY: 473322 AN XY: 724806

Gnomad4 AFR exome AF: 0.889

Gnomad4 AMR exome AF: 0.746

Gnomad4 ASJ exome AF: 0.525

Gnomad4 EAS exome AF: 0.929

Gnomad4 SAS exome AF: 0.762

Gnomad4 FIN exome AF: 0.620

Gnomad4 NFE exome AF: 0.626

Gnomad4 OTH exome AF: 0.665

GnomAD4 genome AF: 0.715 AC: 108833 AN: 152114 Hom.: 40209 Cov.: 32 AF XY: 0.717 AC XY: 53286 AN XY: 74368

Gnomad4 AFR AF: 0.883

Gnomad4 AMR AF: 0.715

Gnomad4 ASJ AF: 0.524

Gnomad4 EAS AF: 0.920

Gnomad4 SAS AF: 0.779

Gnomad4 FIN AF: 0.609

Gnomad4 NFE AF: 0.623

Gnomad4 OTH AF: 0.682

Alfa AF: 0.636 Hom.: 77825

Bravo AF: 0.729

TwinsUK AF: 0.628 AC: 2327

ALSPAC AF: 0.622 AC: 2397

ESP6500AA AF: 0.878 AC: 3869

ESP6500EA AF: 0.619 AC: 5324

ExAC AF: 0.699 AC: 84815

Asia WGS AF: 0.835 AC: 2903 AN: 3478

EpiCase AF: 0.613

EpiControl AF: 0.614

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Benign	0.74
DEOGEN2	Benign	0.086	.;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.0062	T;T;T
MetaRNN	Benign	6.0e-7	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.1	.;N;.
MutationTaster	Benign	0.62	P;P;P
PrimateAI	Benign	0.39	T
PROVEAN	Benign	1.0	N;N;.
REVEL	Benign	0.16
Sift	Benign	0.41	T;T;.
Sift4G	Benign	0.40	T;T;.
Polyphen		0.0	.;B;.
Vest4		0.065
MPC		0.62
ClinPred		0.00088	T
GERP RS		3.1
Varity_R		0.097
gMVP		0.37

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

LitVar

Other links and lift over

dbSNP: rs7302981; hg19: chr12-50537815;