Variant 10-50218534-C-A 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.990G>T(p.Lys330Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ASAH2
NM_019893.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.642

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=0.11304274).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH2	NM_019893.4 linkuse as main transcript	c.990G>T	p.Lys330Asn	missense_variant	8/21	ENST00000682911.1	NP_063946.2	Q9NR71-1
ASAH2	NM_001143974.3 linkuse as main transcript	c.990G>T	p.Lys330Asn	missense_variant	8/20		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.990G>T	p.Lys330Asn	missense_variant	8/21		NM_019893.4	ENSP00000506746.1	Q9NR71-1
ASAH2	ENST00000395526.9 linkuse as main transcript	c.990G>T	p.Lys330Asn	missense_variant	9/22	1		ENSP00000378897.3	Q9NR71-1
ASAH2	ENST00000329428.10 linkuse as main transcript	c.933G>T	p.Lys311Asn	missense_variant	7/19	1		ENSP00000329886.6	A0A0C4DFQ8
ASAH2	ENST00000443575.5 linkuse as main transcript	c.516G>T	p.Lys172Asn	missense_variant	5/18	5		ENSP00000392766.1	E9PBM9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

79318

Hom.:

AF XY:

0.000117

AC XY:

AN XY:

42826

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000594

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:

0.00000274

AC:

AN:

1461498

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727068

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.000131

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

Jul 11, 2023

The c.990G>T (p.K330N) alteration is located in exon 7 (coding exon 7) of the ASAH2 gene. This alteration results from a G to T substitution at nucleotide position 990, causing the lysine (K) at amino acid position 330 to be replaced by an asparagine (N). 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

Uncertain

0.53

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;.;.;.

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.92

D;D;D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Benign

-0.93

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.4

N;N;N;N

REVEL

Benign

0.18

Sift

Benign

0.29

T;T;T;T

Sift4G

Benign

0.31

T;T;T;T

Polyphen

0.93

P;.;D;.

Vest4

0.42

MutPred

0.50

Loss of sheet (P = 0.0104);.;Loss of sheet (P = 0.0104);.;

MVP

0.36

MPC

3.7

ClinPred

0.31

GERP RS

2.1

Varity_R

0.42

gMVP

0.67

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