14-50877959-C-G

Position:

• chr14-50877959-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001206673.2(ABHD12B):​c.112C>G​(p.Pro38Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00073 in 1,523,198 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (2 hom.)
• Consequence: ABHD12B NM_001206673.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07692844).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABHD12B	NM_001206673.2	c.112C>G	p.Pro38Ala	missense_variant	2/13	ENST00000337334.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABHD12B	ENST00000337334.7	c.112C>G	p.Pro38Ala	missense_variant	2/13	1	NM_001206673.2	P1

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

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: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000322 AC: 41 AN: 127338 Hom.: 0 AF XY: 0.000290 AC XY: 20 AN XY: 69054

Gnomad AFR exome AF: 0.000161

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000148

Gnomad NFE exome AF: 0.000727

Gnomad OTH exome AF: 0.000505

GnomAD4 exome AF: 0.000772 AC: 1059 AN: 1370976 Hom.: 2 Cov.: 31 AF XY: 0.000722 AC XY: 488 AN XY: 675472

Gnomad4 AFR exome AF: 0.000195

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: 0.000119

Gnomad4 NFE exome AF: 0.000932

Gnomad4 OTH exome AF: 0.000837

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74408

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000332

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

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

Feb 22, 2023

The c.112C>G (p.P38A) alteration is located in exon 2 (coding exon 2) of the ABHD12B gene. This alteration results from a C to G substitution at nucleotide position 112, causing the proline (P) at amino acid position 38 to be replaced by an alanine (A). 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	0.11
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Benign	0.88
DEOGEN2	Benign	0.0010	T
Eigen	Benign	-0.071
Eigen_PC	Benign	-0.037
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D;D;D;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.10
Sift	Benign	0.19	T
Sift4G	Uncertain	0.059	T
Polyphen		0.80	P
Vest4		0.39
MVP		0.30
MPC		0.11
ClinPred		0.049	T
GERP RS		4.2
Varity_R		0.065
gMVP		0.27

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: rs767199730; hg19: chr14-51344677;