10-50234545-T-G

Variant names:

• chr10-50234545-T-G
• NM_019893.4:c.695A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.74

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=0.22947678).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASAH2	NM_019893.4	c.695A>C	p.Asp232Ala	missense_variant	Exon 6 of 21	ENST00000682911.1	NP_063946.2
ASAH2	NM_001143974.3	c.695A>C	p.Asp232Ala	missense_variant	Exon 6 of 20		NP_001137446.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASAH2	ENST00000682911.1	c.695A>C	p.Asp232Ala	missense_variant	Exon 6 of 21		NM_019893.4	ENSP00000506746.1
ASAH2	ENST00000395526.9	c.695A>C	p.Asp232Ala	missense_variant	Exon 7 of 22	1		ENSP00000378897.3
ASAH2	ENST00000329428.10	c.638A>C	p.Asp213Ala	missense_variant	Exon 5 of 19	1		ENSP00000329886.6
ASAH2	ENST00000443575.5	c.221A>C	p.Asp74Ala	missense_variant	Exon 3 of 18	5		ENSP00000392766.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460728 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726696

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 05, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	23
DANN	Benign	0.92
DEOGEN2	Benign	0.36	T;.;.;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.056
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.80	T;T;T;T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.41	T
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	D
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.

Other links and lift over

hg19: chr10-51994305;