rs2228501

Variant names:

• chr12-48132876-G-A
• rs2228501
• NM_000289.6:c.246G>A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000289.6(PFKM):​c.246G>A​(p.Thr82Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0795 in 1,611,564 control chromosomes in the GnomAD database, including 6,024 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (361 hom., cov: 32)
  • Exomes 𝑓: 0.082 (5663 hom.)
• Consequence: PFKM NM_000289.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.04

Genes affected

PFKM (HGNC:8877): (phosphofructokinase, muscle) Three phosphofructokinase isozymes exist in humans: muscle, liver and platelet. These isozymes function as subunits of the mammalian tetramer phosphofructokinase, which catalyzes the phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate. Tetramer composition varies depending on tissue type. This gene encodes the muscle-type isozyme. Mutations in this gene have been associated with glycogen storage disease type VII, also known as Tarui disease. Alternatively spliced transcript variants have been described.[provided by RefSeq, Nov 2009]

MIR6505 (HGNC:50104): (microRNA 6505) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 12-48132876-G-A is Benign according to our data. Variant chr12-48132876-G-A is described in ClinVar as [Benign]. Clinvar id is 255759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.091 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFKM	NM_000289.6	c.246G>A	p.Thr82Thr	synonymous_variant	Exon 5 of 23	ENST00000359794.11	NP_000280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFKM	ENST00000359794.11	c.246G>A	p.Thr82Thr	synonymous_variant	Exon 5 of 23	1	NM_000289.6	ENSP00000352842.5

Frequencies

GnomAD3 genomes AF: 0.0598 AC: 9099 AN: 152116 Hom.: 361 Cov.: 32

Gnomad AFR AF: 0.0244

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0408

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.0839

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0929

Gnomad OTH AF: 0.0540

GnomAD3 exomes AF: 0.0571 AC: 14072 AN: 246558 Hom.: 590 AF XY: 0.0572 AC XY: 7619 AN XY: 133240

Gnomad AFR exome AF: 0.0202

Gnomad AMR exome AF: 0.0289

Gnomad ASJ exome AF: 0.0150

Gnomad EAS exome AF: 0.000386

Gnomad SAS exome AF: 0.0157

Gnomad FIN exome AF: 0.0827

Gnomad NFE exome AF: 0.0904

Gnomad OTH exome AF: 0.0581

GnomAD4 exome AF: 0.0816 AC: 119092 AN: 1459330 Hom.: 5663 Cov.: 31 AF XY: 0.0795 AC XY: 57689 AN XY: 725796

Gnomad4 AFR exome AF: 0.0201

Gnomad4 AMR exome AF: 0.0301

Gnomad4 ASJ exome AF: 0.0168

Gnomad4 EAS exome AF: 0.000504

Gnomad4 SAS exome AF: 0.0161

Gnomad4 FIN exome AF: 0.0836

Gnomad4 NFE exome AF: 0.0959

Gnomad4 OTH exome AF: 0.0688

GnomAD4 genome AF: 0.0598 AC: 9101 AN: 152234 Hom.: 361 Cov.: 32 AF XY: 0.0582 AC XY: 4329 AN XY: 74430

Gnomad4 AFR AF: 0.0244

Gnomad4 AMR AF: 0.0408

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.0139

Gnomad4 FIN AF: 0.0839

Gnomad4 NFE AF: 0.0929

Gnomad4 OTH AF: 0.0534

Alfa AF: 0.0719 Hom.: 275

Bravo AF: 0.0532

Asia WGS AF: 0.0130 AC: 44 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type VII Benign:4

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

not specified Benign:2

Dec 21, 2015

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 26, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	9.0
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2228501; hg19: chr12-48526659;