12-57230918-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005412.6(SHMT2):c.149C>T(p.Ser50Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,613,948 control chromosomes in the GnomAD database, including 304 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 131 hom., cov: 33)

Exomes 𝑓: 0.010 ( 173 hom. )

Consequence

SHMT2
NM_005412.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.38

Publications

18 publications found

Variant links:

Genes affected

SHMT2 (HGNC:10852): (serine hydroxymethyltransferase 2) This gene encodes the mitochondrial form of a pyridoxal phosphate-dependent enzyme that catalyzes the reversible reaction of serine and tetrahydrofolate to glycine and 5,10-methylene tetrahydrofolate. The encoded product is primarily responsible for glycine synthesis. The activity of the encoded protein has been suggested to be the primary source of intracellular glycine. The gene which encodes the cytosolic form of this enzyme is located on chromosome 17. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

SHMT2 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities
Inheritance: AR Classification: STRONG, LIMITED Submitted by: PanelApp Australia, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
complex neurodevelopmental disorder
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

SHMT2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030794144).

BP6

Variant 12-57230918-C-T is Benign according to our data. Variant chr12-57230918-C-T is described in ClinVar as Benign. ClinVar VariationId is 1272337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0767 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005412.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SHMT2	NM_005412.6	MANE Select	c.149C>T	p.Ser50Leu	missense	Exon 2 of 12	NP_005403.2
SHMT2	NM_001166356.2		c.149C>T	p.Ser50Leu	missense	Exon 2 of 12	NP_001159828.1	P34897-2
SHMT2	NM_001166357.1		c.86C>T	p.Ser29Leu	missense	Exon 2 of 12	NP_001159829.1	P34897-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SHMT2	ENST00000328923.8	TSL:1 MANE Select	c.149C>T	p.Ser50Leu	missense	Exon 2 of 12	ENSP00000333667.3	P34897-1
SHMT2	ENST00000557487.5	TSL:1	c.149C>T	p.Ser50Leu	missense	Exon 2 of 12	ENSP00000452315.1	P34897-2
SHMT2	ENST00000414700.7	TSL:1	c.86C>T	p.Ser29Leu	missense	Exon 2 of 12	ENSP00000406881.3	P34897-3

Frequencies

GnomAD3 genomes

AF:

0.0274

AC:

4161

AN:

152026

Hom.:

131

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0789

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0112

Gnomad ASJ

AF:

0.0156

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00236

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00866

Gnomad OTH

AF:

0.0211

GnomAD2 exomes

AF:

0.0115

AC:

2886

AN:

251410

AF XY:

0.00999

show subpopulations

Gnomad AFR exome

AF:

0.0791

Gnomad AMR exome

AF:

0.00587

Gnomad ASJ exome

AF:

0.0115

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00342

Gnomad NFE exome

AF:

0.00962

Gnomad OTH exome

AF:

0.00929

GnomAD4 exome

AF:

0.0102

AC:

14902

AN:

1461804

Hom.:

173

Cov.:

AF XY:

0.00972

AC XY:

7069

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.0844

AC:

2824

AN:

33476

American (AMR)

AF:

0.00651

AC:

291

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0106

AC:

278

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00214

AC:

185

AN:

86248

European-Finnish (FIN)

AF:

0.00369

AC:

197

AN:

53420

Middle Eastern (MID)

AF:

0.0160

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.00932

AC:

10367

AN:

1112010

Other (OTH)

AF:

0.0111

AC:

669

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

884

1768

2652

3536

4420

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

422

844

1266

1688

2110

<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:

0.0274

AC:

4173

AN:

152144

Hom.:

131

Cov.:

AF XY:

0.0259

AC XY:

1926

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.0790

AC:

3278

AN:

41494

American (AMR)

AF:

0.0112

AC:

171

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0156

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00187

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00236

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00865

AC:

588

AN:

68008

Other (OTH)

AF:

0.0209

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

198

396

593

791

989

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0136

Hom.:

Bravo

AF:

0.0308

TwinsUK

AF:

0.00944

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.0778

AC:

343

ESP6500EA

AF:

0.00837

AC:

ExAC

AF:

0.0129

AC:

1560

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.00774

EpiControl

AF:

0.0103

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0031

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.53

PhyloP100

2.4

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-2.0

REVEL

Benign

0.033

Sift

Benign

0.21

Sift4G

Benign

0.23

Polyphen

0.097

Vest4

0.054

MPC

0.44

ClinPred

0.017

GERP RS

3.9

PromoterAI

-0.0071

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.18

gMVP

0.34

Mutation Taster

=88/12

polymorphism (auto)

(source)

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

Publications

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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