14-50877975-T-A

Variant names:

• chr14-50877975-T-A
• rs184852992
• NM_001206673.2:c.128T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001206673.2(ABHD12B):​c.128T>A​(p.Met43Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000724 in 1,381,778 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M43T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ABHD12B NM_001206673.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00100
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04977995).

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.128T>A	p.Met43Lys	missense	Exon 2 of 13	NP_001193602.1	Q7Z5M8-1
	ABHD12B	NM_181814.2		c.105-2477T>A		intron	N/A	NP_861535.1	Q7Z5M8-2
	ABHD12B	NM_181533.4		c.-89-770T>A		intron	N/A	NP_853511.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABHD12B	ENST00000337334.7	TSL:1 MANE Select	c.128T>A	p.Met43Lys	missense	Exon 2 of 13	ENSP00000336693.2	Q7Z5M8-1
	PYGL	ENST00000532462.5	TSL:1	c.2380-19806A>T		intron	N/A	ENSP00000431657.1	E9PK47
	ABHD12B	ENST00000353130.5	TSL:1	c.105-2477T>A		intron	N/A	ENSP00000343951.1	Q7Z5M8-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.24e-7 AC: 1 AN: 1381778 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 681662

African (AFR) AF: 0.00 AC: 0 AN: 31484

American (AMR) AF: 0.00 AC: 0 AN: 35408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25126

East Asian (EAS) AF: 0.00 AC: 0 AN: 35706

South Asian (SAS) AF: 0.00 AC: 0 AN: 78520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33850

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078208

Other (OTH) AF: 0.00 AC: 0 AN: 57790

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	2.2
DANN	Benign	0.74
DEOGEN2	Benign	0.00077	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.0010
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.061
Sift	Benign	0.50	T
Sift4G	Benign	0.92	T
Polyphen		0.0	B
Vest4		0.28
MutPred		0.67		Gain of catalytic residue at M43 (P = 0.0084)
MVP		0.067
MPC		0.10
ClinPred		0.037	T
GERP RS		1.1
Varity_R		0.15
gMVP		0.25
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs184852992; hg19: chr14-51344693;