20-25294981-G-A

Position:

• chr20-25294981-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015600.5(ABHD12):​c.1207C>T​(p.Leu403Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00588 in 1,614,154 control chromosomes in the GnomAD database, including 329 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (146 hom., cov: 34)
  • Exomes 𝑓: 0.0039 (183 hom.)
• Consequence: ABHD12 NM_015600.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.190

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]

PYGB (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 20-25294981-G-A is Benign according to our data. Variant chr20-25294981-G-A is described in ClinVar as [Benign]. Clinvar id is 1228212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-25294981-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.19 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0808 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYGB	NM_002862.4	c.2313-623G>A		intron_variant		ENST00000216962.9	NP_002853.2
ABHD12	NM_015600.5	c.1207C>T	p.Leu403Leu	synonymous_variant	13/13		NP_056415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYGB	ENST00000216962.9	c.2313-623G>A		intron_variant		1	NM_002862.4	ENSP00000216962.3

Frequencies

GnomAD3 genomes AF: 0.0249 AC: 3782 AN: 152174 Hom.: 146 Cov.: 34

Gnomad AFR AF: 0.0830

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00961

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.0222

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0187

GnomAD3 exomes AF: 0.00924 AC: 2324 AN: 251486 Hom.: 76 AF XY: 0.00800 AC XY: 1088 AN XY: 135922

Gnomad AFR exome AF: 0.0831

Gnomad AMR exome AF: 0.00526

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00326

Gnomad SAS exome AF: 0.0214

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000501

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00389 AC: 5688 AN: 1461862 Hom.: 183 Cov.: 33 AF XY: 0.00408 AC XY: 2967 AN XY: 727228

Gnomad4 AFR exome AF: 0.0841

Gnomad4 AMR exome AF: 0.00575

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00209

Gnomad4 SAS exome AF: 0.0197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000308

Gnomad4 OTH exome AF: 0.00735

GnomAD4 genome AF: 0.0250 AC: 3801 AN: 152292 Hom.: 146 Cov.: 34 AF XY: 0.0237 AC XY: 1766 AN XY: 74458

Gnomad4 AFR AF: 0.0831

Gnomad4 AMR AF: 0.00960

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.0226

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.00855 Hom.: 22

Bravo AF: 0.0279

Asia WGS AF: 0.0190 AC: 66 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.78
DANN	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2500429; hg19: chr20-25275617;