Variant 10-50248547-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_019893.4(ASAH2):c.64G>A(p.Ala22Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,613,466 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

ASAH2
NM_019893.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.19

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.043367386).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH2	NM_019893.4 linkuse as main transcript	c.64G>A	p.Ala22Thr	missense_variant	2/21	ENST00000682911.1	NP_063946.2
ASAH2	NM_001143974.3 linkuse as main transcript	c.64G>A	p.Ala22Thr	missense_variant	2/20		NP_001137446.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASAH2	ENST00000682911.1 linkuse as main transcript	c.64G>A	p.Ala22Thr	missense_variant	2/21		NM_019893.4	ENSP00000506746	P1	Q9NR71-1
ASAH2	ENST00000395526.9 linkuse as main transcript	c.64G>A	p.Ala22Thr	missense_variant	3/22	1		ENSP00000378897	P1	Q9NR71-1
ASAH2	ENST00000329428.10 linkuse as main transcript	c.7G>A	p.Ala3Thr	missense_variant	1/19	1		ENSP00000329886

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000135

AC:

AN:

251212

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135758

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000984

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461324

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727006

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000760

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000590

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000882

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000824

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

Oct 26, 2022

The c.64G>A (p.A22T) alteration is located in exon 1 (coding exon 1) of the ASAH2 gene. This alteration results from a G to A substitution at nucleotide position 64, causing the alanine (A) at amino acid position 22 to be replaced by a threonine (T). 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

0.097

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;.;.

Eigen

Benign

0.0088

Eigen_PC

Benign

0.077

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.77

T;T;T

M_CAP

Benign

0.0039

MetaRNN

Benign

0.043

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;M;.

MutationTaster

Benign

0.97

D;D;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.91

N;N;N

REVEL

Benign

0.087

Sift

Uncertain

0.012

D;D;D

Sift4G

Benign

0.081

T;T;T

Polyphen

0.55

P;P;.

Vest4

0.34

MutPred

0.42

Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);.;

MVP

0.33

MPC

0.071

ClinPred

0.22

GERP RS

5.9

Varity_R

0.14

gMVP

0.68

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