22-41577355-C-A

Variant names:

• chr22-41577355-C-A
• rs150005152
• NM_002676.3:c.752G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002676.3(PMM1):​c.752G>T​(p.Arg251Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R251Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PMM1 NM_002676.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.04
• Publications: 0 publications found

Genes affected

PMM1 (HGNC:9114): (phosphomannomutase 1) Phosphomannomutase catalyzes the conversion between D-mannose 6-phosphate and D-mannose 1-phosphate which is a substrate for GDP-mannose synthesis. GDP-mannose is used for synthesis of dolichol-phosphate-mannose, which is essential for N-linked glycosylation and thus the secretion of several glycoproteins as well as for the synthesis of glycosyl-phosphatidyl-inositol (GPI) anchored proteins. [provided by RefSeq, Jul 2008]

CSDC2 (HGNC:30359): (cold shock domain containing C2) Predicted to enable mRNA 3'-UTR binding activity. Predicted to be involved in regulation of mRNA stability. Predicted to be located in nucleus. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38755184).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002676.3. 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
	PMM1	NM_002676.3	MANE Select	c.752G>T	p.Arg251Leu	missense	Exon 8 of 8	NP_002667.2	Q92871

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMM1	ENST00000216259.8	TSL:1 MANE Select	c.752G>T	p.Arg251Leu	missense	Exon 8 of 8	ENSP00000216259.7	Q92871
	PMM1	ENST00000949539.1		c.986G>T	p.Arg329Leu	missense	Exon 10 of 10	ENSP00000619598.1
	PMM1	ENST00000940470.1		c.881G>T	p.Arg294Leu	missense	Exon 9 of 9	ENSP00000610529.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.26	T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.39	T
MetaSVM	Pathogenic	0.96	D
PhyloP100		3.0
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.15
Sift	Benign	0.055	T
MutPred		0.32		Gain of sheet (P = 0.0011)
MVP		0.76
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.62
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs150005152; hg19: chr22-41973359;