8-144359409-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001363118.2(SLC52A2):​c.116A>G​(p.Lys39Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000385 in 1,611,996 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

SLC52A2
NM_001363118.2 missense

Scores

3
15

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.97
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]
FBXL6 (HGNC:13603): (F-box and leucine rich repeat protein 6) This gene encodes a member of a family of proteins that are characterized by an F-box motif. The encoded protein also contains leucine-rich repeats. F-box-containing proteins comprise one of the subunits of the SCF (SKP1-cullin-F-box) complex, which functions in phosphorylation-dependent ubiquitination. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.20776269).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC52A2NM_001363118.2 linkc.116A>G p.Lys39Arg missense_variant Exon 2 of 5 ENST00000643944.2 NP_001350047.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC52A2ENST00000643944.2 linkc.116A>G p.Lys39Arg missense_variant Exon 2 of 5 NM_001363118.2 ENSP00000496184.2 Q9HAB3

Frequencies

GnomAD3 genomes
AF:
0.0000199
AC:
3
AN:
150408
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.00318
Gnomad NFE
AF:
0.0000296
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000320
AC:
8
AN:
249772
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135292
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:
0.0000710
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000404
AC:
59
AN:
1461484
Hom.:
0
Cov.:
31
AF XY:
0.0000426
AC XY:
31
AN XY:
727048
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000375
Gnomad4 NFE exome
AF:
0.0000495
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000199
AC:
3
AN:
150512
Hom.:
0
Cov.:
33
AF XY:
0.0000136
AC XY:
1
AN XY:
73502
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000296
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000141
Hom.:
0
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.000164
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Brown-Vialetto-van Laere syndrome 2 Uncertain:2
Aug 19, 2021
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research

- -

Oct 28, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 39 of the SLC52A2 protein (p.Lys39Arg). This variant is present in population databases (rs782174760, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with SLC52A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 579817). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Inborn genetic diseases Uncertain:1
Jan 02, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.116A>G (p.K39R) alteration is located in exon 2 (coding exon 1) of the SLC52A2 gene. This alteration results from a A to G substitution at nucleotide position 116, causing the lysine (K) at amino acid position 39 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Benign
0.28
.;T;T;.;T;T;T;T;.;T
Eigen
Benign
0.17
Eigen_PC
Benign
0.059
FATHMM_MKL
Benign
0.51
D
M_CAP
Uncertain
0.19
D
MetaRNN
Benign
0.21
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.36
T
MutationAssessor
Uncertain
2.2
.;M;M;.;M;.;M;M;.;M
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-0.86
N;N;N;N;N;N;N;N;N;.
REVEL
Benign
0.26
Sift
Benign
0.31
T;T;T;T;T;T;T;T;T;.
Sift4G
Benign
0.10
T;T;T;T;T;T;T;T;T;.
Polyphen
1.0
.;D;D;.;D;.;D;D;.;D
Vest4
0.21, 0.20, 0.23
MutPred
0.37
Loss of methylation at K39 (P = 0.0088);Loss of methylation at K39 (P = 0.0088);Loss of methylation at K39 (P = 0.0088);Loss of methylation at K39 (P = 0.0088);Loss of methylation at K39 (P = 0.0088);Loss of methylation at K39 (P = 0.0088);Loss of methylation at K39 (P = 0.0088);Loss of methylation at K39 (P = 0.0088);Loss of methylation at K39 (P = 0.0088);Loss of methylation at K39 (P = 0.0088);
MVP
0.49
MPC
0.091
ClinPred
0.39
T
GERP RS
1.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.11
gMVP
0.18

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs782174760; hg19: chr8-145583069; COSMIC: COSV57350738; COSMIC: COSV57350738; API