2-74210033-G-T

Variant names:

• chr2-74210033-G-T
• rs1384785942
• NM_006636.4:c.654G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_006636.4(MTHFD2):​c.654G>T​(p.Ala218Ala) variant causes a synonymous 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. Synonymous variant affecting the same amino acid position (i.e. A218A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MTHFD2 NM_006636.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -8.02
• Publications: 0 publications found

Genes affected

MTHFD2 (HGNC:7434): (methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2, methenyltetrahydrofolate cyclohydrolase) This gene encodes a nuclear-encoded mitochondrial bifunctional enzyme with methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities. The enzyme functions as a homodimer and is unique in its absolute requirement for magnesium and inorganic phosphate. Formation of the enzyme-magnesium complex allows binding of NAD. Alternative splicing results in two different transcripts, one protein-coding and the other not protein-coding. This gene has a pseudogene on chromosome 7. [provided by RefSeq, Mar 2009]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP7: Synonymous conserved (PhyloP=-8.02 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006636.4. 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
	MTHFD2	NM_006636.4	MANE Select	c.654G>T	p.Ala218Ala	synonymous	Exon 5 of 8	NP_006627.2	P13995-1
	MTHFD2	NM_001410192.1		c.348G>T	p.Ala116Ala	synonymous	Exon 6 of 9	NP_001397121.1	P13995-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD2	ENST00000394053.7	TSL:1 MANE Select	c.654G>T	p.Ala218Ala	synonymous	Exon 5 of 8	ENSP00000377617.2	P13995-1
	MTHFD2	ENST00000677997.1		c.576G>T	p.Ala192Ala	synonymous	Exon 5 of 8	ENSP00000503074.1	A0A7I2V2U6
	MTHFD2	ENST00000409601.1	TSL:5	c.531G>T	p.Ala177Ala	synonymous	Exon 4 of 6	ENSP00000386542.1	B8ZZU9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.059
DANN	Benign	0.86
PhyloP100		-8.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs1384785942; hg19: chr2-74437160;