chr2-74198320-G-T

Position:

• chr2-74198320-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000677997.1(MTHFD2):​c.24-7385G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 145,460 control chromosomes in the GnomAD database, including 2,815 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.21 (1366 hom., cov: 21)
  • Exomes 𝑓: 0.25 (1449 hom.)
• Consequence: MTHFD2 ENST00000677997.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.508

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]

ENSG00000279070 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.74198320G>T		intergenic_region

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFD2	ENST00000677997.1	c.24-7385G>T		intron_variant				ENSP00000503074.1
MTHFD2	ENST00000677170.1	c.-303-3062G>T		intron_variant				ENSP00000503486.1
MTHFD2	ENST00000678684.1	c.-205-7385G>T		intron_variant				ENSP00000504687.1
ENSG00000279070	ENST00000624835.2	n.241C>A		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes AF: 0.211 AC: 17091 AN: 80880 Hom.: 1362 Cov.: 21

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.194

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.233

GnomAD4 exome AF: 0.247 AC: 15896 AN: 64468 Hom.: 1449 Cov.: 0 AF XY: 0.245 AC XY: 7958 AN XY: 32524

Gnomad4 AFR exome AF: 0.121

Gnomad4 AMR exome AF: 0.395

Gnomad4 ASJ exome AF: 0.247

Gnomad4 EAS exome AF: 0.430

Gnomad4 SAS exome AF: 0.170

Gnomad4 FIN exome AF: 0.224

Gnomad4 NFE exome AF: 0.206

Gnomad4 OTH exome AF: 0.238

GnomAD4 genome AF: 0.211 AC: 17107 AN: 80992 Hom.: 1366 Cov.: 21 AF XY: 0.216 AC XY: 8551 AN XY: 39628

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.344

Gnomad4 ASJ AF: 0.233

Gnomad4 EAS AF: 0.451

Gnomad4 SAS AF: 0.196

Gnomad4 FIN AF: 0.231

Gnomad4 NFE AF: 0.209

Gnomad4 OTH AF: 0.235

Alfa AF: 0.105 Hom.: 109

Bravo AF: 0.131

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.6
DANN	Benign	0.65

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs56168672; hg19: chr2-74425447;