12-57231762-CGC-TGT

Variant names:

• chr12-57231762-CGC-TGT
• NM_005412.6:c.361_363delCGCinsTGT
• SHMT2 p.Arg121Cys

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_005412.6(SHMT2):​c.361_363delCGCinsTGT​(p.Arg121Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SHMT2 NM_005412.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18
• Publications: 0 publications found

Genes affected

SHMT2 (HGNC:10852): (serine hydroxymethyltransferase 2) This gene encodes the mitochondrial form of a pyridoxal phosphate-dependent enzyme that catalyzes the reversible reaction of serine and tetrahydrofolate to glycine and 5,10-methylene tetrahydrofolate. The encoded product is primarily responsible for glycine synthesis. The activity of the encoded protein has been suggested to be the primary source of intracellular glycine. The gene which encodes the cytosolic form of this enzyme is located on chromosome 17. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

SHMT2 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• complex neurodevelopmental disorder

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005412.6. 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
	SHMT2	NM_005412.6	MANE Select	c.361_363delCGCinsTGT	p.Arg121Cys	missense	N/A	NP_005403.2
	SHMT2	NM_001166356.2		c.361_363delCGCinsTGT	p.Arg121Cys	missense	N/A	NP_001159828.1	P34897-2
	SHMT2	NM_001166357.1		c.298_300delCGCinsTGT	p.Arg100Cys	missense	N/A	NP_001159829.1	P34897-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHMT2	ENST00000328923.8	TSL:1 MANE Select	c.361_363delCGCinsTGT	p.Arg121Cys	missense	N/A	ENSP00000333667.3	P34897-1
	SHMT2	ENST00000557487.5	TSL:1	c.361_363delCGCinsTGT	p.Arg121Cys	missense	N/A	ENSP00000452315.1	P34897-2
	SHMT2	ENST00000414700.7	TSL:1	c.298_300delCGCinsTGT	p.Arg100Cys	missense	N/A	ENSP00000406881.3	P34897-3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr12-57625545;