10-50245326-G-C

Variant names:

• chr10-50245326-G-C
• NM_019893.4:c.256C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_019893.4(ASAH2):​c.256C>G​(p.Pro86Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: ASAH2 NM_019893.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.227

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]

ACMG classification

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=0.08437607).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASAH2	NM_019893.4	c.256C>G	p.Pro86Ala	missense_variant	Exon 3 of 21	ENST00000682911.1	NP_063946.2
ASAH2	NM_001143974.3	c.256C>G	p.Pro86Ala	missense_variant	Exon 3 of 20		NP_001137446.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASAH2	ENST00000682911.1	c.256C>G	p.Pro86Ala	missense_variant	Exon 3 of 21		NM_019893.4	ENSP00000506746.1
ASAH2	ENST00000395526.9	c.256C>G	p.Pro86Ala	missense_variant	Exon 4 of 22	1		ENSP00000378897.3
ASAH2	ENST00000329428.10	c.199C>G	p.Pro67Ala	missense_variant	Exon 2 of 19	1		ENSP00000329886.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.256C>G (p.P86A) alteration is located in exon 2 (coding exon 2) of the ASAH2 gene. This alteration results from a C to G substitution at nucleotide position 256, causing the proline (P) at amino acid position 86 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	0.057
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	12
DANN	Benign	0.60
DEOGEN2	Benign	0.25	T;.;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.61	T;T;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.084	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.58	N;N;N
REVEL	Benign	0.0090
Sift	Uncertain	0.018	D;D;D
Sift4G	Benign	0.20	T;T;T
Polyphen		0.10	B;B;.
Vest4		0.27
MutPred		0.19		Loss of glycosylation at P86 (P = 0.0631);Loss of glycosylation at P86 (P = 0.0631);.;
MVP		0.055
MPC		0.022
ClinPred		0.12	T
GERP RS		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.029
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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.

Other links and lift over

hg19: chr10-52005086;