Variant 11-74343353-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_173582.6(PGM2L1):c.1282G>T(p.Glu428Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PGM2L1
NM_173582.6 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 3.07

Variant links:

Genes affected

PGM2L1 (HGNC:20898): (phosphoglucomutase 2 like 1) Enables glucose-1,6-bisphosphate synthase activity. Predicted to be involved in glucose metabolic process and phosphorylation. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

PGM2L1 links:

LOC112268078 (HGNC:):

LOC112268078 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-74343353-C-A is Pathogenic according to our data. Variant chr11-74343353-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1008756.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-74343353-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PGM2L1	NM_173582.6 linkuse as main transcript	c.1282G>T	p.Glu428Ter	stop_gained	10/14	ENST00000298198.5
LOC112268078	XR_002957258.2 linkuse as main transcript	n.314+13865C>A		intron_variant, non_coding_transcript_variant
PGM2L1	XM_011544953.4 linkuse as main transcript	c.1345G>T	p.Glu449Ter	stop_gained	11/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGM2L1	ENST00000298198.5 linkuse as main transcript	c.1282G>T	p.Glu428Ter	stop_gained	10/14	1	NM_173582.6	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000406

AC:

AN:

246166

Hom.:

AF XY:

0.00000751

AC XY:

AN XY:

133192

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000340

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1456708

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724666

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000353

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skin abnormalities

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 11, 2023

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 10, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1008756). This premature translational stop signal has been observed in individual(s) with PGM2L1-related conditions (PMID: 33979636). This variant is present in population databases (rs767118518, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Glu428*) in the PGM2L1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PGM2L1 are known to be pathogenic (PMID: 33979636). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Uncertain

0.95

MutationTaster

Benign

1.0

Vest4

0.32

GERP RS

5.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over