Variant 10-50214802-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_019893.4(ASAH2):c.1081C>A(p.Arg361Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. 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.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

ASAH2
NM_019893.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.57

Variant links:

Genes affected

ASAH2 (HGNC:18860): (N-acylsphingosine amidohydrolase 2) Ceramidases (EC 3.5.1.23), such as ASAH2, catalyze hydrolysis of the N-acyl linkage of ceramide, a second messenger in a variety of cellular events, to produce sphingosine. Sphingosine exerts both mitogenic and apoptosis-inducing activities, and its phosphorylated form functions as an intra- and intercellular second messenger (see MIM 603730) (Mitsutake et al., 2001 [PubMed 11328816]).[supplied by OMIM, Mar 2008]

ASAH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.07334617).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH2	NM_019893.4 linkuse as main transcript	c.1081C>A	p.Arg361Ser	missense_variant	9/21	ENST00000682911.1	NP_063946.2	Q9NR71-1
ASAH2	NM_001143974.3 linkuse as main transcript	c.1081C>A	p.Arg361Ser	missense_variant	9/20		NP_001137446.1	Q9NR71-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ASAH2	ENST00000682911.1 linkuse as main transcript	c.1081C>A	p.Arg361Ser	missense_variant	9/21		NM_019893.4	ENSP00000506746.1	Q9NR71-1
ASAH2	ENST00000395526.9 linkuse as main transcript	c.1081C>A	p.Arg361Ser	missense_variant	10/22	1		ENSP00000378897.3	Q9NR71-1
ASAH2	ENST00000329428.10 linkuse as main transcript	c.1024C>A	p.Arg342Ser	missense_variant	8/19	1		ENSP00000329886.6	A0A0C4DFQ8
ASAH2	ENST00000443575.5 linkuse as main transcript	c.607C>A	p.Arg203Ser	missense_variant	6/18	5		ENSP00000392766.1	E9PBM9

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000623

AC:

AN:

128346

Hom.:

AF XY:

0.0000730

AC XY:

AN XY:

68534

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00101

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461420

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727030

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000328

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2024

The c.1081C>A (p.R361S) alteration is located in exon 8 (coding exon 8) of the ASAH2 gene. This alteration results from a C to A substitution at nucleotide position 1081, causing the arginine (R) at amino acid position 361 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

0.15

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.37

T;.;.;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.73

T;T;T;T

M_CAP

Benign

0.0078

MetaRNN

Benign

0.073

T;T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.5

N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.40

T;T;T;T

Sift4G

Benign

0.41

T;T;T;T

Polyphen

0.0

B;.;B;.

Vest4

0.19

MutPred

0.41

Gain of disorder (P = 0.0258);.;Gain of disorder (P = 0.0258);.;

MVP

0.18

MPC

2.1

ClinPred

0.042

GERP RS

5.3

Varity_R

0.17

gMVP

0.49

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over