2-168765629-G-T

Variant names:

• chr2-168765629-G-T
• rs758828764
• NM_203463.3:c.883G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_203463.3(CERS6):​c.883G>T​(p.Val295Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CERS6 NM_203463.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.50

Genes affected

CERS6 (HGNC:23826): (ceramide synthase 6) Enables sphingosine N-acyltransferase activity. Involved in ceramide biosynthetic process. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37524012).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CERS6	NM_203463.3	c.883G>T	p.Val295Phe	missense_variant	Exon 9 of 10	ENST00000305747.11	NP_982288.1
CERS6	NM_001256126.2	c.883G>T	p.Val295Phe	missense_variant	Exon 9 of 11		NP_001243055.1
CERS6	XM_017003749.3	c.460G>T	p.Val154Phe	missense_variant	Exon 6 of 8		XP_016859238.1
CERS6	XM_005246440.6	c.307G>T	p.Val103Phe	missense_variant	Exon 6 of 8		XP_005246497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CERS6	ENST00000305747.11	c.883G>T	p.Val295Phe	missense_variant	Exon 9 of 10	2	NM_203463.3	ENSP00000306579.6
CERS6	ENST00000392687.4	c.883G>T	p.Val295Phe	missense_variant	Exon 9 of 11	1		ENSP00000376453.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251344 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135840

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461724 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727150

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	20
DANN	Benign	0.84
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.48	N;N
REVEL	Uncertain	0.50
Sift	Benign	0.36	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.11	B;.
Vest4		0.54
MutPred		0.47		Loss of catalytic residue at V295 (P = 0.1152);Loss of catalytic residue at V295 (P = 0.1152);
MVP		0.76
MPC		0.71
ClinPred		0.27	T
GERP RS		2.0
Varity_R		0.044
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs758828764; hg19: chr2-169622139; COSMIC: COSV59837242;