7-44062819-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000290.4(PGAM2):c.707A>C(p.Glu236Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000459 in 1,614,202 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00033 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00047 (8 hom.)
• Consequence: PGAM2 NM_000290.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3 O:1
• Conservation: PhyloP100: 7.79

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027874857).
• BP6: Variant 7-44062819-T-G is Benign according to our data. Variant chr7-44062819-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 440991.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, not_provided=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000472 (690/1461890) while in subpopulation MID AF= 0.0132 (76/5768). AF 95% confidence interval is 0.0108. There are 8 homozygotes in gnomad4_exome. There are 440 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGAM2	NM_000290.4	c.707A>C	p.Glu236Ala	missense_variant	3/3	ENST00000297283.4
DBNL	NM_001014436.3	c.*1903T>G		3_prime_UTR_variant	13/13	ENST00000448521.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGAM2	ENST00000297283.4	c.707A>C	p.Glu236Ala	missense_variant	3/3	1	NM_000290.4	P1
DBNL	ENST00000448521.6	c.*1903T>G		3_prime_UTR_variant	13/13	1	NM_001014436.3	P4
DBNL	ENST00000432854.5	c.*1903T>G		3_prime_UTR_variant	11/11	5

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152194 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000696 AC: 175 AN: 251420 Hom.: 0 AF XY: 0.000964 AC XY: 131 AN XY: 135894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00421

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000325

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000472 AC: 690 AN: 1461890 Hom.: 8 Cov.: 31 AF XY: 0.000605 AC XY: 440 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00405

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000195

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152312 Hom.: 1 Cov.: 33 AF XY: 0.000443 AC XY: 33 AN XY: 74472

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000327 Hom.: 0

Bravo AF: 0.000298

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000799 AC: 97

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glycogen storage disease type X Benign:2 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

- -

PGAM2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 25, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Uncertain	0.13
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.011
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.54
Sift	Benign	0.32	T
Sift4G	Benign	0.32	T
Polyphen		0.0030	B
Vest4		0.67
MVP		0.91
MPC		0.13
ClinPred		0.095	T
GERP RS		5.0
Varity_R		0.36
gMVP		0.69

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: rs140230479; hg19: chr7-44102418; COSMIC: COSV51978712; COSMIC: COSV51978712;