NM_017614.5:c.1010+2010A>C

Variant names:

• chr5-79085866-A-C
• rs625879
• NM_017614.5:c.1010+2010A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017614.5(BHMT2):​c.1010+2010A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 151,932 control chromosomes in the GnomAD database, including 22,238 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 (22238 hom., cov: 31)
• Consequence: BHMT2 NM_017614.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.612
• Publications: 17 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.609 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BHMT2	NM_017614.5	MANE Select	c.1010+2010A>C		intron	N/A	NP_060084.2
	BHMT2	NM_001178005.2		c.818+2010A>C		intron	N/A	NP_001171476.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BHMT2	ENST00000255192.8	TSL:1 MANE Select	c.1010+2010A>C		intron	N/A	ENSP00000255192.3
	BHMT2	ENST00000521567.1	TSL:2	c.818+2010A>C		intron	N/A	ENSP00000430278.1
	DMGDH	ENST00000520388.5	TSL:4	n.606+18298T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.521 AC: 79040 AN: 151814 Hom.: 22226 Cov.: 31

Gnomad AFR AF: 0.292

Gnomad AMI AF: 0.768

Gnomad AMR AF: 0.591

Gnomad ASJ AF: 0.445

Gnomad EAS AF: 0.612

Gnomad SAS AF: 0.517

Gnomad FIN AF: 0.672

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.614

Gnomad OTH AF: 0.532

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

GnomAD4 genome AF: 0.521 AC: 79088 AN: 151932 Hom.: 22238 Cov.: 31 AF XY: 0.523 AC XY: 38817 AN XY: 74252

African (AFR) AF: 0.292 AC: 12113 AN: 41448

American (AMR) AF: 0.592 AC: 9038 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 1543 AN: 3466

East Asian (EAS) AF: 0.611 AC: 3147 AN: 5152

South Asian (SAS) AF: 0.519 AC: 2494 AN: 4802

European-Finnish (FIN) AF: 0.672 AC: 7089 AN: 10556

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

European-Non Finnish (NFE) AF: 0.614 AC: 41680 AN: 67926

Other (OTH) AF: 0.529 AC: 1113 AN: 2104

Alfa AF: 0.581 Hom.: 16334

Bravo AF: 0.505

Asia WGS AF: 0.541 AC: 1884 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.6
DANN	Benign	0.69
PhyloP100		-0.61
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: rs625879; hg19: chr5-78381689;