chr15-89175938-C-A

Variant names:

• chr15-89175938-C-A
• rs1209430757
• NM_152924.5:c.665C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152924.5(ABHD2):​c.665C>A​(p.Ala222Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A222G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABHD2 NM_152924.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.95
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13224393).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152924.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABHD2	NM_152924.5	MANE Select	c.665C>A	p.Ala222Glu	missense	Exon 6 of 11	NP_690888.1	A0A024RC89
	ABHD2	NM_001416412.1		c.665C>A	p.Ala222Glu	missense	Exon 8 of 13	NP_001403341.1	A0A024RC89
	ABHD2	NM_001416413.1		c.665C>A	p.Ala222Glu	missense	Exon 9 of 14	NP_001403342.1	A0A024RC89

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABHD2	ENST00000352732.10	TSL:1 MANE Select	c.665C>A	p.Ala222Glu	missense	Exon 6 of 11	ENSP00000268129.5	P08910
	ABHD2	ENST00000565973.5	TSL:5	c.665C>A	p.Ala222Glu	missense	Exon 10 of 15	ENSP00000455639.1	P08910
	ABHD2	ENST00000864961.1		c.665C>A	p.Ala222Glu	missense	Exon 5 of 10	ENSP00000535020.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.17	N
PhyloP100		4.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.13
Sift	Benign	0.74	T
Sift4G	Benign	0.92	T
Polyphen		0.015	B
Vest4		0.27
MutPred		0.39		Gain of disorder (P = 0.0157)
MVP		0.20
MPC		0.74
ClinPred		0.36	T
GERP RS		5.5
Varity_R		0.13
gMVP		0.39

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

Other links and lift over

dbSNP: rs1209430757; hg19: chr15-89719169;