14-50872245-C-A

Position:

• chr14-50872245-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001206673.2(ABHD12B):​c.71C>A​(p.Ala24Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000359 in 1,392,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000032 (0 hom.)
• Consequence: ABHD12B NM_001206673.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.818

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18422878).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABHD12B	NM_001206673.2	c.71C>A	p.Ala24Asp	missense_variant	1/13	ENST00000337334.7	NP_001193602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABHD12B	ENST00000337334.7	c.71C>A	p.Ala24Asp	missense_variant	1/13	1	NM_001206673.2	ENSP00000336693	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.00000322 AC: 4 AN: 1240788 Hom.: 0 Cov.: 32 AF XY: 0.00000328 AC XY: 2 AN XY: 609290

Gnomad4 AFR exome AF: 0.0000783

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000333

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000199

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74294

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

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: 0.00

Bravo AF: 0.00000378

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

Jul 08, 2022

The c.71C>A (p.A24D) alteration is located in exon 1 (coding exon 1) of the ABHD12B gene. This alteration results from a C to A substitution at nucleotide position 71, causing the alanine (A) at amino acid position 24 to be replaced by an aspartic acid (D). 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	0.20
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0027	.;T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.48	T;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	0.60	D;D;N;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.072
Sift	Benign	0.051	T;T
Sift4G	Benign	0.32	T;T
Polyphen		0.83	P;P
Vest4		0.34
MutPred		0.39		Gain of catalytic residue at M29 (P = 5e-04);Gain of catalytic residue at M29 (P = 5e-04);
MVP		0.31
MPC		0.16
ClinPred		0.90	D
GERP RS		3.7
Varity_R		0.25
gMVP		0.43

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: rs1036893896; hg19: chr14-51338963;