12-50136009-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_147190.5(CERS5):c.697A>C(p.Ile233Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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)
• Consequence: CERS5 NM_147190.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.760

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21783283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CERS5	NM_147190.5	c.697A>C	p.Ile233Leu	missense_variant	7/10	ENST00000317551.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CERS5	ENST00000317551.12	c.697A>C	p.Ile233Leu	missense_variant	7/10	2	NM_147190.5	P1
	ENST00000548468.2	n.105+23708T>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Feb 05, 2024

The c.697A>C (p.I233L) alteration is located in exon 7 (coding exon 7) of the CERS5 gene. This alteration results from a A to C substitution at nucleotide position 697, causing the isoleucine (I) at amino acid position 233 to be replaced by a leucine (L). 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	Benign	0.094
BayesDel_addAF	Benign	0.0022	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	19
Dann	Benign	0.96
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.84	T;T;D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.78	T
MutationTaster	Benign	0.97	N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.1	N;N;.
REVEL	Benign	0.22
Sift	Benign	0.076	T;T;.
Sift4G	Benign	0.28	T;T;.
Polyphen		0.022	.;B;.
Vest4		0.23
MutPred		0.45		.;Gain of catalytic residue at R238 (P = 0.0107);.;
MVP		0.63
MPC		0.35
ClinPred		0.31	T
GERP RS		1.9
Varity_R		0.056
gMVP		0.50

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: rs367900841; hg19: chr12-50529792;