20-25294985-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The ENST00000376542.8(ABHD12):c.1203A>G(p.Ser401=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0427 in 1,614,130 control chromosomes in the GnomAD database, including 1,698 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.052 (222 hom., cov: 34)
  • Exomes 𝑓: 0.042 (1476 hom.)
• Consequence: ABHD12 ENST00000376542.8 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.379

Genes affected

ABHD12 (HGNC:15868): (abhydrolase domain containing 12, lysophospholipase) This gene encodes an enzyme that catalyzes the hydrolysis of 2-arachidonoyl glycerol (2-AG), the main endocannabinoid lipid transmitter that acts on cannabinoid receptors, CB1 and CB2. The endocannabinoid system is involved in a wide range of physiological processes, including neurotransmission, mood, appetite, pain appreciation, addiction behavior, and inflammation. Mutations in this gene are associated with the neurodegenerative disease, PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract), resulting from an inborn error of endocannabinoid metabolism. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.[provided by RefSeq, Jan 2011]

PYGB (HGNC:9723): (glycogen phosphorylase B) The protein encoded by this gene is a glycogen phosphorylase found predominantly in the brain. The encoded protein forms homodimers which can associate into homotetramers, the enzymatically active form of glycogen phosphorylase. The activity of this enzyme is positively regulated by AMP and negatively regulated by ATP, ADP, and glucose-6-phosphate. This enzyme catalyzes the rate-determining step in glycogen degradation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 20-25294985-T-C is Benign according to our data. Variant chr20-25294985-T-C is described in ClinVar as [Benign]. Clinvar id is 1269367.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-25294985-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.379 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYGB	NM_002862.4	c.2313-619T>C		intron_variant		ENST00000216962.9
ABHD12	NM_015600.5	c.1203A>G	p.Ser401=	synonymous_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYGB	ENST00000216962.9	c.2313-619T>C		intron_variant		1	NM_002862.4	P1

Frequencies

GnomAD3 genomes AF: 0.0519 AC: 7892 AN: 152188 Hom.: 222 Cov.: 34

Gnomad AFR AF: 0.0715

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.0442

Gnomad ASJ AF: 0.0450

Gnomad EAS AF: 0.0640

Gnomad SAS AF: 0.0267

Gnomad FIN AF: 0.0603

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0406

Gnomad OTH AF: 0.0493

GnomAD3 exomes AF: 0.0472 AC: 11860 AN: 251476 Hom.: 310 AF XY: 0.0461 AC XY: 6272 AN XY: 135914

Gnomad AFR exome AF: 0.0732

Gnomad AMR exome AF: 0.0382

Gnomad ASJ exome AF: 0.0497

Gnomad EAS exome AF: 0.0651

Gnomad SAS exome AF: 0.0319

Gnomad FIN exome AF: 0.0637

Gnomad NFE exome AF: 0.0440

Gnomad OTH exome AF: 0.0474

GnomAD4 exome AF: 0.0417 AC: 60954 AN: 1461824 Hom.: 1476 Cov.: 33 AF XY: 0.0412 AC XY: 29940 AN XY: 727214

Gnomad4 AFR exome AF: 0.0721

Gnomad4 AMR exome AF: 0.0405

Gnomad4 ASJ exome AF: 0.0489

Gnomad4 EAS exome AF: 0.0763

Gnomad4 SAS exome AF: 0.0313

Gnomad4 FIN exome AF: 0.0629

Gnomad4 NFE exome AF: 0.0389

Gnomad4 OTH exome AF: 0.0442

GnomAD4 genome AF: 0.0519 AC: 7902 AN: 152306 Hom.: 222 Cov.: 34 AF XY: 0.0537 AC XY: 3997 AN XY: 74466

Gnomad4 AFR AF: 0.0714

Gnomad4 AMR AF: 0.0443

Gnomad4 ASJ AF: 0.0450

Gnomad4 EAS AF: 0.0641

Gnomad4 SAS AF: 0.0269

Gnomad4 FIN AF: 0.0603

Gnomad4 NFE AF: 0.0406

Gnomad4 OTH AF: 0.0507

Alfa AF: 0.0473 Hom.: 100

Bravo AF: 0.0526

Asia WGS AF: 0.0520 AC: 183 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 24, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.64
Dann	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs73598373; hg19: chr20-25275621; COSMIC: COSV53822754;