7-44065189-A-C

Position:

• chr7-44065189-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000297283.4(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 ENST00000297283.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.25

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]

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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. Variant chr7-44065189-A-C is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
PGAM2	NM_000290.4	c.341T>G	p.Ile114Ser	missense_variant	1/3	ENST00000297283.4	NP_000281.2
DBNL	NM_001014436.3	c.*4273A>C		3_prime_UTR_variant	13/13	ENST00000448521.6	NP_001014436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PGAM2	ENST00000297283.4	c.341T>G	p.Ile114Ser	missense_variant	1/3	1	NM_000290.4	ENSP00000297283	P1
DBNL	ENST00000448521.6	c.*4273A>C		3_prime_UTR_variant	13/13	1	NM_001014436.3	ENSP00000411701	P4
	ENST00000445938.1	n.282A>C		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.0271 AC: 4129 AN: 152088 Hom.: 130 Cov.: 33

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

GnomAD3 exomes AF: 0.0273 AC: 6860 AN: 251284 Hom.: 250 AF XY: 0.0301 AC XY: 4089 AN XY: 135866

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 SAS exome AF: 0.0977

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.: 35 AF XY: 0.0170 AC XY: 12397 AN XY: 727206

Gnomad4 AFR exome AF: 0.0667

Gnomad4 AMR exome AF: 0.0185

Gnomad4 ASJ exome AF: 0.0346

Gnomad4 EAS exome AF: 0.0428

Gnomad4 SAS exome AF: 0.0957

Gnomad4 FIN exome AF: 0.000750

Gnomad4 NFE exome AF: 0.00511

Gnomad4 OTH exome AF: 0.0239

GnomAD4 genome AF: 0.0272 AC: 4146 AN: 152206 Hom.: 132 Cov.: 33 AF XY: 0.0282 AC XY: 2100 AN XY: 74418

Gnomad4 AFR AF: 0.0596

Gnomad4 AMR AF: 0.0172

Gnomad4 ASJ AF: 0.0357

Gnomad4 EAS AF: 0.0487

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00622

Gnomad4 OTH AF: 0.0336

Alfa AF: 0.0139 Hom.: 68

Bravo AF: 0.0288

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.0502 AC: 221

ESP6500EA AF: 0.00628 AC: 54

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

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 13, 2017	- -

Glycogen storage disease type X Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.34
MPC		0.51
ClinPred		0.013	T
GERP RS		5.9
Varity_R		0.87
gMVP		0.80

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: rs61756062; hg19: chr7-44104788;