10-50245377-C-T

Variant summary

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

The NM_019893.4(ASAH2):​c.205G>A​(p.Ala69Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,818 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 (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

ASAH2
NM_019893.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.522
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]

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=0.0635626).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ASAH2NM_019893.4 linkc.205G>A p.Ala69Thr missense_variant Exon 3 of 21 ENST00000682911.1 NP_063946.2 Q9NR71-1
ASAH2NM_001143974.3 linkc.205G>A p.Ala69Thr missense_variant Exon 3 of 20 NP_001137446.1 Q9NR71-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ASAH2ENST00000682911.1 linkc.205G>A p.Ala69Thr missense_variant Exon 3 of 21 NM_019893.4 ENSP00000506746.1 Q9NR71-1
ASAH2ENST00000395526.9 linkc.205G>A p.Ala69Thr missense_variant Exon 4 of 22 1 ENSP00000378897.3 Q9NR71-1
ASAH2ENST00000329428.10 linkc.148G>A p.Ala50Thr missense_variant Exon 2 of 19 1 ENSP00000329886.6 A0A0C4DFQ8

Frequencies

GnomAD3 genomes
AF:
0.00000659
AC:
1
AN:
151818
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00000398
AC:
1
AN:
251310
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135814
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
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
Cov.:
31
GnomAD4 genome
AF:
0.00000659
AC:
1
AN:
151818
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74136
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
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
Bravo
AF:
0.00000378
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 24, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.205G>A (p.A69T) alteration is located in exon 2 (coding exon 2) of the ASAH2 gene. This alteration results from a G to A substitution at nucleotide position 205, causing the alanine (A) at amino acid position 69 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
0.066
BayesDel_addAF
Benign
-0.54
T
BayesDel_noAF
Benign
-0.83
CADD
Benign
0.81
DANN
Benign
0.45
DEOGEN2
Benign
0.24
T;.;.
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.0081
N
LIST_S2
Benign
0.37
T;T;T
M_CAP
Benign
0.0026
T
MetaRNN
Benign
0.064
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.14
N;N;.
PrimateAI
Benign
0.19
T
PROVEAN
Benign
-0.21
N;N;N
REVEL
Benign
0.0080
Sift
Benign
0.34
T;T;T
Sift4G
Benign
0.43
T;T;T
Polyphen
0.0
B;B;.
Vest4
0.11
MVP
0.040
MPC
0.021
ClinPred
0.047
T
GERP RS
-2.6
Varity_R
0.029
gMVP
0.35

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.

Other links and lift over

dbSNP: rs377466392; hg19: chr10-52005137; API