5-79077608-C-T

Variant names:

• chr5-79077608-C-T
• rs682985
• NM_017614.5:c.162C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_017614.5(BHMT2):​c.162C>T​(p.Asp54Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.588 in 1,612,500 control chromosomes in the GnomAD database, including 284,133 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 0.52 (22139 hom., cov: 29)
  • Exomes 𝑓: 0.59 (261994 hom.)
• Consequence: BHMT2 NM_017614.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.65
• Publications: 39 publications found

Genes affected

BHMT2 (HGNC:1048): (betaine--homocysteine S-methyltransferase 2) Homocysteine is a sulfur-containing amino acid that plays a crucial role in methylation reactions. Transfer of the methyl group from betaine to homocysteine creates methionine, which donates the methyl group to methylate DNA, proteins, lipids, and other intracellular metabolites. The protein encoded by this gene is one of two methyl transferases that can catalyze the transfer of the methyl group from betaine to homocysteine. Anomalies in homocysteine metabolism have been implicated in disorders ranging from vascular disease to neural tube birth defects such as spina bifida. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2010]

DMGDH (HGNC:24475): (dimethylglycine dehydrogenase) This gene encodes an enzyme involved in the catabolism of choline, catalyzing the oxidative demethylation of dimethylglycine to form sarcosine. The enzyme is found as a monomer in the mitochondrial matrix, and uses flavin adenine dinucleotide and folate as cofactors. Mutation in this gene causes dimethylglycine dehydrogenase deficiency, characterized by a fishlike body odor, chronic muscle fatigue, and elevated levels of the muscle form of creatine kinase in serum. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

DMGDH Gene-Disease associations (from GenCC):

• dimethylglycine dehydrogenase deficiency

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP7: Synonymous conserved (PhyloP=-1.65 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.606 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017614.5. 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
	BHMT2	NM_017614.5	MANE Select	c.162C>T	p.Asp54Asp	synonymous	Exon 2 of 8	NP_060084.2
	BHMT2	NM_001178005.2		c.162C>T	p.Asp54Asp	synonymous	Exon 2 of 7	NP_001171476.1	Q9H2M3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BHMT2	ENST00000255192.8	TSL:1 MANE Select	c.162C>T	p.Asp54Asp	synonymous	Exon 2 of 8	ENSP00000255192.3	Q9H2M3-1
	BHMT2	ENST00000518666.5	TSL:5	c.-19C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 5	ENSP00000428640.1	E5RH96
	BHMT2	ENST00000896185.1		c.162C>T	p.Asp54Asp	synonymous	Exon 2 of 8	ENSP00000566244.1

Frequencies

GnomAD3 genomes AF: 0.519 AC: 78748 AN: 151618 Hom.: 22127 Cov.: 29

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.769

Gnomad AMR AF: 0.595

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.613

Gnomad SAS AF: 0.521

Gnomad FIN AF: 0.672

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.611

Gnomad OTH AF: 0.531

GnomAD2 exomes AF: 0.574 AC: 143761 AN: 250584 AF XY: 0.577

Gnomad AFR exome AF: 0.281

Gnomad AMR exome AF: 0.599

Gnomad ASJ exome AF: 0.440

Gnomad EAS exome AF: 0.628

Gnomad FIN exome AF: 0.663

Gnomad NFE exome AF: 0.613

Gnomad OTH exome AF: 0.566

GnomAD4 exome AF: 0.595 AC: 868680 AN: 1460762 Hom.: 261994 Cov.: 42 AF XY: 0.593 AC XY: 430866 AN XY: 726702

African (AFR) AF: 0.262 AC: 8781 AN: 33458

American (AMR) AF: 0.591 AC: 26382 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 11604 AN: 26122

East Asian (EAS) AF: 0.567 AC: 22506 AN: 39690

South Asian (SAS) AF: 0.512 AC: 44079 AN: 86122

European-Finnish (FIN) AF: 0.660 AC: 35206 AN: 53360

Middle Eastern (MID) AF: 0.528 AC: 3038 AN: 5752

European-Non Finnish (NFE) AF: 0.614 AC: 682676 AN: 1111246

Other (OTH) AF: 0.570 AC: 34408 AN: 60340

GnomAD4 genome AF: 0.519 AC: 78794 AN: 151738 Hom.: 22139 Cov.: 29 AF XY: 0.522 AC XY: 38732 AN XY: 74152

African (AFR) AF: 0.288 AC: 11912 AN: 41312

American (AMR) AF: 0.595 AC: 9080 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 1554 AN: 3470

East Asian (EAS) AF: 0.612 AC: 3150 AN: 5144

South Asian (SAS) AF: 0.523 AC: 2506 AN: 4792

European-Finnish (FIN) AF: 0.672 AC: 7083 AN: 10544

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.611 AC: 41527 AN: 67922

Other (OTH) AF: 0.529 AC: 1113 AN: 2102

Alfa AF: 0.574 Hom.: 53911

Bravo AF: 0.504

Asia WGS AF: 0.548 AC: 1906 AN: 3478

EpiCase AF: 0.601

EpiControl AF: 0.606

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.020
DANN	Benign	0.65
PhyloP100		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs682985; hg19: chr5-78373431; COSMIC: COSV54873278; COSMIC: COSV54873278;