12-50135993-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_147190.5(CERS5):c.713G>A(p.Arg238Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 1,369,954 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: 31)
  • Exomes 𝑓: 0.0000066 (0 hom.)
• Consequence: CERS5 NM_147190.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CERS5	NM_147190.5	c.713G>A	p.Arg238Gln	missense_variant	7/10	ENST00000317551.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CERS5	ENST00000317551.12	c.713G>A	p.Arg238Gln	missense_variant	7/10	2	NM_147190.5	P1
	ENST00000548468.2	n.105+23692C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000113 AC: 2 AN: 177494 Hom.: 0 AF XY: 0.0000215 AC XY: 2 AN XY: 93190

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000634

Gnomad SAS exome AF: 0.0000701

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000657 AC: 9 AN: 1369954 Hom.: 0 Cov.: 30 AF XY: 0.0000104 AC XY: 7 AN XY: 672628

Gnomad4 AFR exome AF: 0.0000660

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000768

Gnomad4 SAS exome AF: 0.0000145

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000280

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ExAC AF: 0.0000170 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 02, 2023

The c.713G>A (p.R238Q) alteration is located in exon 7 (coding exon 7) of the CERS5 gene. This alteration results from a G to A substitution at nucleotide position 713, causing the arginine (R) at amino acid position 238 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	0.91	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-4.0	D;D;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0020	D;D;.
Sift4G	Uncertain	0.0030	D;D;.
Polyphen		1.0	.;D;.
Vest4		0.86
MutPred		0.79		.;Gain of catalytic residue at R238 (P = 0.0045);.;
MVP		0.89
MPC		1.2
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.64
gMVP		0.88

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: rs765182768; hg19: chr12-50529776;