rs143764492

Variant names:

• chr14-50880523-G-C
• rs143764492
• NM_001206673.2:c.407G>C

Your query was ambiguous. Multiple possible variants found:

• chr14-50880523-G-C
• chr14-50880523-G-A
• chr14-50880523-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001206673.2(ABHD12B):​c.407G>C​(p.Arg136Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,608,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R136C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ABHD12B NM_001206673.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.17
• Publications: 0 publications found

Genes affected

ABHD12B (HGNC:19837): (abhydrolase domain containing 12B) Predicted to enable acylglycerol lipase activity; lysophospholipase activity; and palmitoyl-(protein) hydrolase activity. Predicted to be involved in monoacylglycerol catabolic process and phosphatidylserine catabolic process. Predicted to be active in endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

PYGL (HGNC:9725): (glycogen phosphorylase L) This gene encodes a homodimeric protein that catalyses the cleavage of alpha-1,4-glucosidic bonds to release glucose-1-phosphate from liver glycogen stores. This protein switches from inactive phosphorylase B to active phosphorylase A by phosphorylation of serine residue 15. Activity of this enzyme is further regulated by multiple allosteric effectors and hormonal controls. Humans have three glycogen phosphorylase genes that encode distinct isozymes that are primarily expressed in liver, brain and muscle, respectively. The liver isozyme serves the glycemic demands of the body in general while the brain and muscle isozymes supply just those tissues. In glycogen storage disease type VI, also known as Hers disease, mutations in liver glycogen phosphorylase inhibit the conversion of glycogen to glucose and results in moderate hypoglycemia, mild ketosis, growth retardation and hepatomegaly. Alternative splicing results in multiple transcript variants encoding different isoforms.[provided by RefSeq, Feb 2011]

PYGL Gene-Disease associations (from GenCC):

• glycogen storage disease VI

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02050069).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001206673.2. 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
	ABHD12B	NM_001206673.2	MANE Select	c.407G>C	p.Arg136Pro	missense	Exon 4 of 13	NP_001193602.1	Q7Z5M8-1
	ABHD12B	NM_181814.2		c.176G>C	p.Arg59Pro	missense	Exon 2 of 11	NP_861535.1	Q7Z5M8-2
	ABHD12B	NM_181533.4		c.86G>C	p.Arg29Pro	missense	Exon 3 of 12	NP_853511.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABHD12B	ENST00000337334.7	TSL:1 MANE Select	c.407G>C	p.Arg136Pro	missense	Exon 4 of 13	ENSP00000336693.2	Q7Z5M8-1
	ABHD12B	ENST00000353130.5	TSL:1	c.176G>C	p.Arg59Pro	missense	Exon 2 of 11	ENSP00000343951.1	Q7Z5M8-2
	PYGL	ENST00000532462.5	TSL:1	c.2380-22354C>G		intron	N/A	ENSP00000431657.1	E9PK47

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000366 AC: 9 AN: 246192 AF XY: 0.0000150

Gnomad AFR exome AF: 0.000379

Gnomad AMR exome AF: 0.0000899

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1456162 Hom.: 0 Cov.: 32 AF XY: 0.00000414 AC XY: 3 AN XY: 724350

African (AFR) AF: 0.0000603 AC: 2 AN: 33160

American (AMR) AF: 0.0000906 AC: 4 AN: 44156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39178

South Asian (SAS) AF: 0.00 AC: 0 AN: 85520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108948

Other (OTH) AF: 0.0000166 AC: 1 AN: 60094

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74476

African (AFR) AF: 0.000313 AC: 13 AN: 41550

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000945

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000576 AC: 7

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.32
DANN	Benign	0.93
DEOGEN2	Benign	0.0077	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.9	L
PhyloP100		-1.2
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.093
Sift	Benign	0.27	T
Sift4G	Benign	0.26	T
Polyphen		0.054	B
Vest4		0.33
MVP		0.24
MPC		0.21
ClinPred		0.016	T
GERP RS		-5.6
Varity_R		0.17
gMVP		0.58
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs143764492; hg19: chr14-51347241;