chr14-50881627-G-T

Variant names:

• chr14-50881627-G-T
• rs138523238
• NM_001206673.2:c.486+1G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PVS1_Moderate PP3 BP6_Moderate BS2

The NM_001206673.2(ABHD12B):​c.486+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00834 in 1,608,000 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0064 (7 hom., cov: 29)
  • Exomes 𝑓: 0.0085 (77 hom.)
• Consequence: ABHD12B NM_001206673.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.00

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

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.028466484 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.8, offset of -6, new splice context is: ctgGTaaag. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP3: Multiple lines of computational evidence support a deleterious effect 5: Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, Eigen [when BayesDel_addAF, MutationTaster was below the threshold]
• BP6: Variant 14-50881627-G-T is Benign according to our data. Variant chr14-50881627-G-T is described in ClinVar as [Benign]. Clinvar id is 3024734.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABHD12B	NM_001206673.2	c.486+1G>T		splice_donor_variant, intron_variant	Intron 5 of 12	ENST00000337334.7	NP_001193602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABHD12B	ENST00000337334.7	c.486+1G>T		splice_donor_variant, intron_variant	Intron 5 of 12	1	NM_001206673.2	ENSP00000336693.2

Frequencies

GnomAD3 genomes AF: 0.00644 AC: 948 AN: 147302 Hom.: 7 Cov.: 29

Gnomad AFR AF: 0.00155

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00232

Gnomad ASJ AF: 0.000290

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000650

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.00346

GnomAD2 exomes AF: 0.00723 AC: 1815 AN: 251000 AF XY: 0.00702

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0116

Gnomad NFE exome AF: 0.0126

Gnomad OTH exome AF: 0.00719

GnomAD4 exome AF: 0.00853 AC: 12461 AN: 1460584 Hom.: 77 Cov.: 36 AF XY: 0.00819 AC XY: 5951 AN XY: 726622

Gnomad4 AFR exome AF: 0.00123 AC: 41 AN: 33424

Gnomad4 AMR exome AF: 0.000985 AC: 44 AN: 44660

Gnomad4 ASJ exome AF: 0.000383 AC: 10 AN: 26096

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39670

Gnomad4 SAS exome AF: 0.000580 AC: 50 AN: 86204

Gnomad4 FIN exome AF: 0.0118 AC: 632 AN: 53378

Gnomad4 NFE exome AF: 0.0102 AC: 11362 AN: 1111068

Gnomad4 Remaining exome AF: 0.00534 AC: 322 AN: 60328

GnomAD4 genome AF: 0.00643 AC: 948 AN: 147416 Hom.: 7 Cov.: 29 AF XY: 0.00605 AC XY: 431 AN XY: 71284

Gnomad4 AFR AF: 0.00155 AC: 0.00155016 AN: 0.00155016

Gnomad4 AMR AF: 0.00232 AC: 0.00231955 AN: 0.00231955

Gnomad4 ASJ AF: 0.000290 AC: 0.00029036 AN: 0.00029036

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000650 AC: 0.000650477 AN: 0.000650477

Gnomad4 FIN AF: 0.0129 AC: 0.0128849 AN: 0.0128849

Gnomad4 NFE AF: 0.0107 AC: 0.0107233 AN: 0.0107233

Gnomad4 OTH AF: 0.00342 AC: 0.00342466 AN: 0.00342466

Alfa AF: 0.00858 Hom.: 24

Bravo AF: 0.00545

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00930 AC: 80

ExAC AF: 0.00855 AC: 1038

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00749

EpiControl AF: 0.00949

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PYGL: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	30
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.1
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs138523238; hg19: chr14-51348345; COSMIC: COSV105221692; COSMIC: COSV105221692;