Variant 10-50234545-T-G 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.695A>C(p.Asp232Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ASAH2
NM_019893.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.74

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:

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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=0.22947678).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASAH2	NM_019893.4 linkuse as main transcript	c.695A>C	p.Asp232Ala	missense_variant	6/21	ENST00000682911.1
ASAH2	NM_001143974.3 linkuse as main transcript	c.695A>C	p.Asp232Ala	missense_variant	6/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASAH2	ENST00000682911.1 linkuse as main transcript	c.695A>C	p.Asp232Ala	missense_variant	6/21		NM_019893.4	P1	Q9NR71-1
ASAH2	ENST00000395526.9 linkuse as main transcript	c.695A>C	p.Asp232Ala	missense_variant	7/22	1		P1	Q9NR71-1
ASAH2	ENST00000329428.10 linkuse as main transcript	c.638A>C	p.Asp213Ala	missense_variant	5/19	1
ASAH2	ENST00000443575.5 linkuse as main transcript	c.221A>C	p.Asp74Ala	missense_variant	3/18	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460728

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726696

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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

Cov.:

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 05, 2021

The c.695A>C (p.D232A) alteration is located in exon 5 (coding exon 5) of the ASAH2 gene. This alteration results from a A to C substitution at nucleotide position 695, causing the aspartic acid (D) at amino acid position 232 to be replaced by an alanine (A). 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

0.18

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.36

T;.;.;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.056

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.80

T;T;T;T

M_CAP

Benign

0.0098

MetaRNN

Benign

0.23

T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.5

D;N;N;N

REVEL

Benign

0.082

Sift

Benign

0.72

T;T;T;T

Sift4G

Benign

0.63

T;T;T;T

Polyphen

0.0030

B;.;B;.

Vest4

0.29

MutPred

0.56

Gain of ubiquitination at K229 (P = 0.0554);.;Gain of ubiquitination at K229 (P = 0.0554);.;

MVP

0.35

MPC

2.3

ClinPred

0.84

GERP RS

4.5

Varity_R

0.43

gMVP

0.56

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over