rs117500243

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_001363118.2(SLC52A2):c.353C>A(p.Ala118Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00397 in 1,613,714 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A118P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0028 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0041 ( 20 hom. )

Consequence

SLC52A2
NM_001363118.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:11

Conservation

PhyloP100: 3.85

Publications

13 publications found

Variant links:

Genes affected

SLC52A2 (HGNC:30224): (solute carrier family 52 member 2) This gene encodes a membrane protein which belongs to the riboflavin transporter family. In humans, riboflavin must be obtained by intestinal absorption because it cannot be synthesized by the body. The water-soluble vitamin riboflavin is processed to the coenzymes flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) which then act as intermediaries in many cellular metabolic reactions. Paralogous members of the riboflavin transporter gene family are located on chromosomes 17 and 20. Unlike other members of this family, this gene has higher expression in brain tissue than small intestine. Alternative splicing of this gene results in multiple transcript variants encoding the same protein. Mutations in this gene have been associated with Brown-Vialetto-Van Laere syndrome 2 - an autosomal recessive progressive neurologic disorder characterized by deafness, bulbar dysfunction, and axial and limb hypotonia. [provided by RefSeq, Jul 2012]

SLC52A2 Gene-Disease associations (from GenCC):

Brown-Vialetto-van Laere syndrome 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P

SLC52A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_001363118.2

BP4

Computational evidence support a benign effect (MetaRNN=0.012701243).

BP6

Variant 8-144359845-C-A is Benign according to our data. Variant chr8-144359845-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 372996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00282 (429/152322) while in subpopulation NFE AF = 0.00462 (314/68024). AF 95% confidence interval is 0.0042. There are 2 homozygotes in GnomAd4. There are 190 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC52A2	NM_001363118.2 link	c.353C>A	p.Ala118Asp	missense_variant	Exon 3 of 5	ENST00000643944.2	NP_001350047.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC52A2	ENST00000643944.2 link	c.353C>A	p.Ala118Asp	missense_variant	Exon 3 of 5		NM_001363118.2	ENSP00000496184.2		Q9HAB3

Frequencies

GnomAD3 genomes

AF:

0.00282

AC:

429

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00462

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00274

AC:

689

AN:

251100

AF XY:

0.00278

show subpopulations

Gnomad AFR exome

AF:

0.000555

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.00914

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00440

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00409

AC:

5979

AN:

1461392

Hom.:

Cov.:

AF XY:

0.00394

AC XY:

2863

AN XY:

726992

show subpopulations

African (AFR)

AF:

0.000926

AC:

AN:

33480

American (AMR)

AF:

0.00143

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00953

AC:

249

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000835

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000359

AC:

AN:

52944

Middle Eastern (MID)

AF:

0.00728

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00474

AC:

5272

AN:

1111998

Other (OTH)

AF:

0.00381

AC:

230

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

408

816

1225

1633

2041

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

200

400

600

800

1000

<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:

0.00282

AC:

429

AN:

152322

Hom.:

Cov.:

AF XY:

0.00255

AC XY:

190

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000698

AC:

AN:

41568

American (AMR)

AF:

0.000719

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0107

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000621

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00462

AC:

314

AN:

68024

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

100

125

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:

0.00386

Hom.:

Bravo

AF:

0.00280

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00407

AC:

ExAC

AF:

0.00285

AC:

346

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00458

EpiControl

AF:

0.00474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Jun 22, 2022

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SLC52A2: BP4, BS2 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Brown-Vialetto-van Laere syndrome 2

Benign:3

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 03, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1Benign:1

Aug 23, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ala118Asp in exon 3 of SLC52A2: This variant is not expected to have clinical significance because it has been identified in 0.46% (303/66400) of European chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs117500243). -

Jul 25, 2016

GeneDx

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

A variant of uncertain significance has been identified in the SLC52A2 gene. The A118D variant has been reported previously as a benign variant; however, additional information was not provided (Yonezawa et al., 2013). The A118D variant is observed in 303/66400 (0.5%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A118D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

SLC52A2-related disorder

Benign:1

Aug 24, 2021

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases

Benign:1

Jul 23, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Uncertain

0.45

T;T;T;T;T;T;T

Eigen

Benign

-0.081

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.89

M_CAP

Pathogenic

0.57

MetaRNN

Benign

0.013

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.099

MutationAssessor

Uncertain

2.5

M;M;M;.;M;M;M

PhyloP100

3.9

PrimateAI

Benign

0.48

PROVEAN

Benign

-2.0

N;N;N;N;N;N;.

REVEL

Uncertain

0.49

Sift

Uncertain

0.0060

D;D;D;D;D;D;.

Sift4G

Uncertain

0.020

D;D;D;T;D;D;.

Polyphen

0.81

P;P;P;.;P;P;P

Vest4

0.60

MVP

0.62

MPC

0.30

ClinPred

0.028

GERP RS

3.5

Varity_R

0.30

gMVP

0.87

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over