chr8-144360427-T-C

Position:

chr8-144360427-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_001363118.2(SLC52A2):c.935T>C(p.Leu312Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000859 in 1,606,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

SLC52A2
NM_001363118.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 6.19

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001363118.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

PP5

Variant 8-144360427-T-C is Pathogenic according to our data. Variant chr8-144360427-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 210041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144360427-T-C is described in UniProt as null. Variant chr8-144360427-T-C is described in UniProt as null. Variant chr8-144360427-T-C is described in UniProt as null. Variant chr8-144360427-T-C is described in UniProt as null. Variant chr8-144360427-T-C is described in UniProt as null. Variant chr8-144360427-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC52A2	NM_001363118.2 linkuse as main transcript	c.935T>C	p.Leu312Pro	missense_variant	3/5	ENST00000643944.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC52A2	ENST00000643944.2 linkuse as main transcript	c.935T>C	p.Leu312Pro	missense_variant	3/5		NM_001363118.2	P1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152284

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000245

AC:

AN:

245242

Hom.:

AF XY:

0.0000300

AC XY:

AN XY:

133536

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000445

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000901

AC:

131

AN:

1454084

Hom.:

Cov.:

AF XY:

0.0000732

AC XY:

AN XY:

723638

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000115

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000566

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Brown-Vialetto-van Laere syndrome 2

Pathogenic:2Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 22, 2022	Variant summary: GPR172A (SLC52A2) c.935T>C (p.Leu312Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 276638 control chromosomes (gnomAD). c.935T>C has been reported in the literature as a biallelic genotype in individuals affected with Brown-Vialetto Laere Syndrome (e.g. Foley_2014, Manole_2017, Marioli_2020). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (e.g. Foley_2014, Console_2022). The most pronounced variant effect results in approximately 40-50% of normal 3H-Riboflavin transport activity and displays a reduced binding affinity compared to the wildtype protein. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as either pathogenic (n=2) or likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 08, 2023	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 312 of the SLC52A2 protein (p.Leu312Pro). This variant is present in population databases (rs754320812, gnomAD 0.005%). This missense change has been observed in individuals with Brown-Vialetto-Van Laere syndrome (PMID: 24253200, 29053833). ClinVar contains an entry for this variant (Variation ID: 210041). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC52A2 protein function. Experimental studies have shown that this missense change affects SLC52A2 function (PMID: 24253200). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 19, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2024	Observed with a pathogenic or likely pathogenic SLC52A2 variant in individuals with Brown-Vialetto-Van Laere syndrome, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 24253200, 29053833); Published functional studies demonstrate a damaging effect: reduced riboflavin uptake and reduced riboflavin transporter protein expression (PMID: 24253200); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26633542, 34428344, 29053833, 24253200) -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2023

The c.935T>C (p.L312P) alteration is located in exon 3 (coding exon 2) of the SLC52A2 gene. This alteration results from a T to C substitution at nucleotide position 935, causing the leucine (L) at amino acid position 312 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of 0.003% (7/276638) total alleles studied. The highest observed frequency was 0.014% (1/7158) of Other alleles. This alteration has been reported in the homozygous state, and in conjunction with another alteration in SLC52A2, in multiple individuals with clinical features of Brown-Vialetto-Van Laere syndrome (Foley, 2014; Manole, 2017; Allison, 2017; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In vitro functional analysis of the p.L312P alteration showed a moderate decrease in 3H-transport activity compared with wild-type SLC52A2 (Foley, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

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

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.55

MutationAssessor

Pathogenic

3.3

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

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-6.8

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

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0010

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.98

MVP

0.83

MPC

0.69

ClinPred

0.94

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.94

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over