rs61756062

Variant names:

• chr7-44065189-A-C
• rs61756062
• NM_000290.4:c.341T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.25
• Publications: 11 publications found

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]

ENSG00000239775 (HGNC:):

ACMG classification

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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000290.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAM2	NM_000290.4	MANE Select	c.341T>G	p.Ile114Ser	missense	Exon 1 of 3	NP_000281.2	P15259
	DBNL	NM_001014436.3	MANE Select	c.*4273A>C		3_prime_UTR	Exon 13 of 13	NP_001014436.1	Q9UJU6-1
	DBNL	NM_001122956.2		c.*4273A>C		3_prime_UTR	Exon 13 of 13	NP_001116428.1	Q9UJU6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAM2	ENST00000297283.4	TSL:1 MANE Select	c.341T>G	p.Ile114Ser	missense	Exon 1 of 3	ENSP00000297283.3	P15259
	DBNL	ENST00000448521.6	TSL:1 MANE Select	c.*4273A>C		3_prime_UTR	Exon 13 of 13	ENSP00000411701.1	Q9UJU6-1
	PGAM2	ENST00000971360.1		c.341T>G	p.Ile114Ser	missense	Exon 1 of 3	ENSP00000641419.1

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

GnomAD2 exomes AF: 0.0273 AC: 6860 AN: 251284 AF XY: 0.0301

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

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: 40 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

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

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: 7 AN: 10610

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.00622 AC: 423 AN: 68002

Other (OTH) AF: 0.0336 AC: 71 AN: 2112

Alfa AF: 0.0152 Hom.: 186

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Glycogen storage disease type X (2)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		7.2
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
PromoterAI		-0.043	Neutral
Varity_R		0.87
gMVP		0.80
Mutation Taster		=71/29	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61756062; hg19: chr7-44104788; COSMIC: COSV107385358; COSMIC: COSV107385358;