10-50248490-G-A

Position:

• chr10-50248490-G-A

Variant summary

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

The NM_019893.4(ASAH2):​c.121C>T​(p.His41Tyr) 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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ASAH2 NM_019893.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0840

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=0.11367601).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH2	NM_019893.4	c.121C>T	p.His41Tyr	missense_variant	2/21	ENST00000682911.1	NP_063946.2
ASAH2	NM_001143974.3	c.121C>T	p.His41Tyr	missense_variant	2/20		NP_001137446.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASAH2	ENST00000682911.1	c.121C>T	p.His41Tyr	missense_variant	2/21		NM_019893.4	ENSP00000506746.1
ASAH2	ENST00000395526.9	c.121C>T	p.His41Tyr	missense_variant	3/22	1		ENSP00000378897.3
ASAH2	ENST00000329428.10	c.64C>T	p.His22Tyr	missense_variant	1/19	1		ENSP00000329886.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2024

The c.121C>T (p.H41Y) alteration is located in exon 1 (coding exon 1) of the ASAH2 gene. This alteration results from a C to T substitution at nucleotide position 121, causing the histidine (H) at amino acid position 41 to be replaced by a tyrosine (Y). 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	0.090
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T;.;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.64	T;T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.13	N;N;N
REVEL	Benign	0.034
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.48	P;B;.
Vest4		0.26
MutPred		0.36		Loss of disorder (P = 0.0406);Loss of disorder (P = 0.0406);.;
MVP		0.24
MPC		0.022
ClinPred		0.13	T
GERP RS		0.0015
Varity_R		0.050
gMVP		0.36

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

Other links and lift over

dbSNP: rs922133248; hg19: chr10-52008250;