5-79077492-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017614.5(BHMT2):c.46C>T(p.Arg16Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000317 in 1,611,278 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R16H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

BHMT2
NM_017614.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.72

Publications

1 publications found

Variant links:

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]

BHMT2 links:

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

DMGDH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.46C>T	p.Arg16Cys	missense	Exon 2 of 8	NP_060084.2
	BHMT2	NM_001178005.2		c.46C>T	p.Arg16Cys	missense	Exon 2 of 7	NP_001171476.1	Q9H2M3-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BHMT2	ENST00000255192.8	TSL:1 MANE Select	c.46C>T	p.Arg16Cys	missense	Exon 2 of 8	ENSP00000255192.3	Q9H2M3-1
BHMT2	ENST00000896185.1		c.46C>T	p.Arg16Cys	missense	Exon 2 of 8	ENSP00000566244.1
BHMT2	ENST00000896179.1		c.46C>T	p.Arg16Cys	missense	Exon 2 of 8	ENSP00000566238.1

Frequencies

GnomAD3 genomes

AF:

0.0000400

AC:

AN:

149992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000735

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000663

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00325

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000399

AC:

AN:

250788

AF XY:

0.0000516

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1461260

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

726942

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33460

American (AMR)

AF:

0.000157

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000270

AC:

AN:

1111652

Other (OTH)

AF:

0.0000166

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000400

AC:

AN:

150018

Hom.:

Cov.:

AF XY:

0.0000274

AC XY:

AN XY:

73002

show subpopulations

African (AFR)

AF:

0.0000734

AC:

AN:

40884

American (AMR)

AF:

0.0000662

AC:

AN:

15108

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5116

South Asian (SAS)

AF:

0.00

AC:

AN:

4732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9762

Middle Eastern (MID)

AF:

0.00355

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67680

Other (OTH)

AF:

0.00

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000843

Hom.:

ExAC

AF:

0.0000494

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.16

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.45

MetaSVM

Benign

-0.29

MutationAssessor

Pathogenic

3.3

PhyloP100

4.7

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-7.3

REVEL

Benign

0.27

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.25

MutPred

0.67

Loss of disorder (P = 0.0135)

MVP

0.71

MPC

0.84

ClinPred

0.94

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.80

gMVP

0.88

Mutation Taster

=63/37

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over