NM_000290.4:c.341T>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000290.4(PGAM2):c.341T>G(p.Ile114Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 1,613,994 control chromosomes in the GnomAD database, including 827 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I114I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.027 ( 132 hom., cov: 33)

Exomes 𝑓: 0.015 ( 695 hom. )

Consequence

PGAM2
NM_000290.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 7.25

Publications

11 publications found

Variant links:

Genes affected

PGAM2 (HGNC:8889): (phosphoglycerate mutase 2) Phosphoglycerate mutase (PGAM) catalyzes the reversible reaction of 3-phosphoglycerate (3-PGA) to 2-phosphoglycerate (2-PGA) in the glycolytic pathway. The PGAM is a dimeric enzyme containing, in different tissues, different proportions of a slow-migrating muscle (MM) isozyme, a fast-migrating brain (BB) isozyme, and a hybrid form (MB). This gene encodes muscle-specific PGAM subunit. Mutations in this gene cause muscle phosphoglycerate mutase eficiency, also known as glycogen storage disease X. [provided by RefSeq, Sep 2009]

PGAM2 links:

DBNL (HGNC:2696): (drebrin like) Enables cadherin binding activity. Predicted to be involved in several processes, including Rac protein signal transduction; nervous system development; and podosome assembly. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

DBNL links:

ENSG00000239775 (HGNC:):

ENSG00000239775 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0065627396).

BP6

Variant 7-44065189-A-C is Benign according to our data. Variant chr7-44065189-A-C is described in ClinVar as [Benign]. Clinvar id is 360276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0968 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGAM2	NM_000290.4 link	c.341T>G	p.Ile114Ser	missense_variant	Exon 1 of 3	ENST00000297283.4	NP_000281.2	P15259
DBNL	NM_001014436.3 link	c.*4273A>C		3_prime_UTR_variant	Exon 13 of 13	ENST00000448521.6	NP_001014436.1	Q9UJU6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGAM2	ENST00000297283.4 link	c.341T>G	p.Ile114Ser	missense_variant	Exon 1 of 3	1	NM_000290.4	ENSP00000297283.3		P15259
DBNL	ENST00000448521.6 link	c.*4273A>C		3_prime_UTR_variant	Exon 13 of 13	1	NM_001014436.3	ENSP00000411701.1		Q9UJU6-1

Frequencies

GnomAD3 genomes

AF:

0.0271

AC:

4129

AN:

152088

Hom.:

130

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0595

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0172

Gnomad ASJ

AF:

0.0357

Gnomad EAS

AF:

0.0488

Gnomad SAS

AF:

0.103

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.00622

Gnomad OTH

AF:

0.0335

GnomAD2 exomes

AF:

0.0273

AC:

6860

AN:

251284

AF XY:

0.0301

show subpopulations

Gnomad AFR exome

AF:

0.0612

Gnomad AMR exome

AF:

0.0181

Gnomad ASJ exome

AF:

0.0345

Gnomad EAS exome

AF:

0.0506

Gnomad FIN exome

AF:

0.000694

Gnomad NFE exome

AF:

0.00700

Gnomad OTH exome

AF:

0.0267

GnomAD4 exome

AF:

0.0148

AC:

21562

AN:

1461788

Hom.:

695

Cov.:

AF XY:

0.0170

AC XY:

12397

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.0667

AC:

2233

AN:

33480

American (AMR)

AF:

0.0185

AC:

827

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0346

AC:

904

AN:

26136

East Asian (EAS)

AF:

0.0428

AC:

1700

AN:

39700

South Asian (SAS)

AF:

0.0957

AC:

8257

AN:

86258

European-Finnish (FIN)

AF:

0.000750

AC:

AN:

53322

Middle Eastern (MID)

AF:

0.0832

AC:

480

AN:

5768

European-Non Finnish (NFE)

AF:

0.00511

AC:

5678

AN:

1112008

Other (OTH)

AF:

0.0239

AC:

1443

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

1533

3066

4600

6133

7666

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

348

696

1044

1392

1740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0272

AC:

4146

AN:

152206

Hom.:

132

Cov.:

AF XY:

0.0282

AC XY:

2100

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.0596

AC:

2475

AN:

41526

American (AMR)

AF:

0.0172

AC:

263

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0357

AC:

124

AN:

3470

East Asian (EAS)

AF:

0.0487

AC:

252

AN:

5174

South Asian (SAS)

AF:

0.104

AC:

503

AN:

4820

European-Finnish (FIN)

AF:

0.000660

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00622

AC:

423

AN:

68002

Other (OTH)

AF:

0.0336

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

197

394

592

789

986

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0152

Hom.:

186

Bravo

AF:

0.0288

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.0502

AC:

221

ESP6500EA

AF:

0.00628

AC:

ExAC

AF:

0.0289

AC:

3505

Asia WGS

AF:

0.0690

AC:

239

AN:

3478

EpiCase

AF:

0.0112

EpiControl

AF:

0.0111

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 01, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Mar 13, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Glycogen storage disease type X

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.66

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.0066

MetaSVM

Benign

-0.50

MutationAssessor

Uncertain

2.4

PhyloP100

7.2

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-5.4

REVEL

Uncertain

0.59

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.0030

Polyphen

0.99

Vest4

0.34

MPC

0.51

ClinPred

0.013

GERP RS

5.9

PromoterAI

-0.043

Neutral

(source)

Varity_R

0.87

gMVP

0.80

Mutation Taster

=71/29

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over