rs797045202

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5

The NM_001363118.2(SLC52A2):​c.1088C>T​(p.Pro363Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000619 in 1,452,854 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P363A) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

SLC52A2
NM_001363118.2 missense

Scores

8
9
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 7.76

Publications

2 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr8-144360675-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 430446.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.955
PP5
Variant 8-144360676-C-T is Pathogenic according to our data. Variant chr8-144360676-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210042.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC52A2NM_001363118.2 linkc.1088C>T p.Pro363Leu missense_variant Exon 4 of 5 ENST00000643944.2 NP_001350047.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC52A2ENST00000643944.2 linkc.1088C>T p.Pro363Leu missense_variant Exon 4 of 5 NM_001363118.2 ENSP00000496184.2 Q9HAB3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD2 exomes
AF:
0.00
AC:
0
AN:
243152
AF XY:
0.00
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000619
AC:
9
AN:
1452854
Hom.:
0
Cov.:
45
AF XY:
0.00000553
AC XY:
4
AN XY:
723004
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33468
American (AMR)
AF:
0.00
AC:
0
AN:
44630
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26034
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39686
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86132
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
45648
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
0.00000720
AC:
8
AN:
1111230
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60264
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.481
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
33
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Brown-Vialetto-van Laere syndrome 2 Pathogenic:1Uncertain:1
Sep 07, 2020
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been reported in combination with a second, rare SLC52A2 variant in an individual affected with  Brown-Vialetto-Van Laere syndrome (PMID: 29053833). ClinVar contains an entry for this variant (Variation ID: 210042). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 363 of the SLC52A2 protein (p.Pro363Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. -

Dec 13, 2019
Baylor Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.38
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Uncertain
0.13
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.51
D;D;D;D;D;D
Eigen
Pathogenic
0.71
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Pathogenic
0.99
D
M_CAP
Pathogenic
0.34
D
MetaRNN
Pathogenic
0.95
D;D;D;D;D;D
MetaSVM
Uncertain
0.20
D
MutationAssessor
Pathogenic
3.3
M;M;M;M;M;M
PhyloP100
7.8
PrimateAI
Uncertain
0.58
T
PROVEAN
Pathogenic
-8.5
D;D;D;D;D;.
REVEL
Pathogenic
0.76
Sift
Uncertain
0.0010
D;D;D;D;D;.
Sift4G
Uncertain
0.0030
D;D;D;D;D;.
Polyphen
1.0
D;D;D;D;D;D
Vest4
0.83
MutPred
0.80
Loss of glycosylation at P363 (P = 0.0189);Loss of glycosylation at P363 (P = 0.0189);Loss of glycosylation at P363 (P = 0.0189);Loss of glycosylation at P363 (P = 0.0189);Loss of glycosylation at P363 (P = 0.0189);Loss of glycosylation at P363 (P = 0.0189);
MVP
0.66
MPC
0.54
ClinPred
1.0
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.60
gMVP
0.83
Mutation Taster
=0/100
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs797045202; hg19: chr8-145584336; API