14-50880523-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02050069).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABHD12B	NM_001206673.2	c.407G>C	p.Arg136Pro	missense_variant	4/13	ENST00000337334.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABHD12B	ENST00000337334.7	c.407G>C	p.Arg136Pro	missense_variant	4/13	1	NM_001206673.2	P1

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

GnomAD3 exomes AF: 0.0000366 AC: 9 AN: 246192 Hom.: 0 AF XY: 0.0000150 AC XY: 2 AN XY: 133226

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 SAS 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

Gnomad4 AFR exome AF: 0.0000603

Gnomad4 AMR exome AF: 0.0000906

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.0000166

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

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Bravo AF: 0.0000945

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000576 AC: 7

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

May 06, 2022

The c.407G>C (p.R136P) alteration is located in exon 4 (coding exon 4) of the ABHD12B gene. This alteration results from a G to C substitution at nucleotide position 407, causing the arginine (R) at amino acid position 136 to be replaced by a proline (P). 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	0.30
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	0.32
Dann	Benign	0.93
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.021	T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.093
Sift	Benign	0.27	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.054	B;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs143764492; hg19: chr14-51347241;