chr12-57230839-A-G

Variant names:

• chr12-57230839-A-G
• rs2037284991
• NM_005412.6:c.70A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005412.6(SHMT2):​c.70A>G​(p.Ile24Val) 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SHMT2 NM_005412.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.75
• 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: PanelApp Australia, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• complex neurodevelopmental disorder

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.021687299).

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.70A>G	p.Ile24Val	missense	Exon 2 of 12	NP_005403.2
	SHMT2	NM_001166356.2		c.70A>G	p.Ile24Val	missense	Exon 2 of 12	NP_001159828.1	P34897-2
	SHMT2	NM_001166357.1		c.7A>G	p.Ile3Val	missense	Exon 2 of 12	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.70A>G	p.Ile24Val	missense	Exon 2 of 12	ENSP00000333667.3	P34897-1
	SHMT2	ENST00000557487.5	TSL:1	c.70A>G	p.Ile24Val	missense	Exon 2 of 12	ENSP00000452315.1	P34897-2
	SHMT2	ENST00000414700.7	TSL:1	c.7A>G	p.Ile3Val	missense	Exon 2 of 12	ENSP00000406881.3	P34897-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.014
DANN	Benign	0.72
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.81	N
PhyloP100		-1.8
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.018
Sift	Benign	0.87	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.073
MutPred		0.31		Gain of disorder (P = 0.1177)
MVP		0.22
MPC		0.41
ClinPred		0.027	T
GERP RS		-7.5
PromoterAI		0.031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.023
gMVP		0.19
Mutation Taster		=96/4	polymorphism

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: rs2037284991; hg19: chr12-57624622;