1-150966173-T-C

Variant names:

• chr1-150966173-T-C
• rs141621672
• NM_022075.5:c.1118A>G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_022075.5(CERS2):​c.1118A>G​(p.Asn373Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000814 in 1,609,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N373D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: CERS2 NM_022075.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.802

Genes affected

CERS2 (HGNC:14076): (ceramide synthase 2) This gene encodes a protein that has sequence similarity to yeast longevity assurance gene 1. Mutation or overexpression of the related gene in yeast has been shown to alter yeast lifespan. The human protein may play a role in the regulation of cell growth. Alternatively spliced transcript variants encoding the same protein have been described. [provided by RefSeq, Jul 2008]

ENSG00000259357 (HGNC:58295):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027754307).
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CERS2	NM_022075.5	c.1118A>G	p.Asn373Ser	missense_variant	Exon 11 of 11	ENST00000368954.10	NP_071358.1
CERS2	NM_181746.4	c.1118A>G	p.Asn373Ser	missense_variant	Exon 11 of 11		NP_859530.1
CERS2	XM_011509451.3	c.1178A>G	p.Asn393Ser	missense_variant	Exon 11 of 11		XP_011507753.1
CERS2	XM_011509452.4	c.1118A>G	p.Asn373Ser	missense_variant	Exon 11 of 11		XP_011507754.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CERS2	ENST00000368954.10	c.1118A>G	p.Asn373Ser	missense_variant	Exon 11 of 11	1	NM_022075.5	ENSP00000357950.5

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000817 AC: 20 AN: 244928 Hom.: 0 AF XY: 0.0000904 AC XY: 12 AN XY: 132780

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.000248

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000985

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000831 AC: 121 AN: 1456826 Hom.: 0 Cov.: 35 AF XY: 0.0000855 AC XY: 62 AN XY: 724912

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.000164

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000918

Gnomad4 OTH exome AF: 0.000183

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74484

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000115 Hom.: 0

Bravo AF: 0.0000642

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1118A>G (p.N373S) alteration is located in exon 11 (coding exon 10) of the CERS2 gene. This alteration results from a A to G substitution at nucleotide position 1118, causing the asparagine (N) at amino acid position 373 to be replaced by a serine (S). 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	0.12
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	13
DANN	Benign	0.88
DEOGEN2	Benign	0.21	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.96
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.76	T;.
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.028	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.91	N;N
REVEL	Benign	0.053
Sift	Benign	0.66	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.0010	B;B
Vest4		0.041
MVP		0.19
MPC		0.46
ClinPred		0.0087	T
GERP RS		-1.7
Varity_R		0.036
gMVP		0.17

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: rs141621672; hg19: chr1-150938649;