15-89195415-C-A

Variant summary

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

The NM_152924.5(ABHD2):c.1270C>A(p.Leu424Met) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABHD2 NM_152924.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.32

Genes affected

ABHD2 (HGNC:18717): (abhydrolase domain containing 2, acylglycerol lipase) This gene encodes a protein containing an alpha/beta hydrolase fold, which is a catalytic domain found in a wide range of enzymes. The encoded protein is an acylglycerol lipase that catalyzes the hydrolysis of endocannabinoid arachidonoylglycerol from the cell membrane. This leads to activation of the sperm calcium channel CatSper, which results in sperm activation. Alternative splicing of this gene results in two transcript variants encoding the same protein. [provided by RefSeq, Jan 2017]

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=0.1070593).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABHD2	NM_152924.5	c.1270C>A	p.Leu424Met	missense_variant	11/11	ENST00000352732.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABHD2	ENST00000352732.10	c.1270C>A	p.Leu424Met	missense_variant	11/11	1	NM_152924.5	P1
ABHD2	ENST00000565973.5	c.1270C>A	p.Leu424Met	missense_variant	15/15	5		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Aug 28, 2023

The c.1270C>A (p.L424M) alteration is located in exon 15 (coding exon 9) of the ABHD2 gene. This alteration results from a C to A substitution at nucleotide position 1270, causing the leucine (L) at amino acid position 424 to be replaced by a methionine (M). 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	0.070
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	17
Dann	Uncertain	0.98
DEOGEN2	Benign	0.062	T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.016
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.24	N;N
REVEL	Benign	0.072
Sift	Benign	0.096	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.070	B;B
Vest4		0.098
MutPred		0.30		Gain of solvent accessibility (P = 0.0026);Gain of solvent accessibility (P = 0.0026);
MVP		0.23
MPC		0.68
ClinPred		0.22	T
GERP RS		4.0
Varity_R		0.054
gMVP		0.47

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: chr15-89738646;