8-144360343-C-T

Variant names:

• chr8-144360343-C-T
• rs398123067
• NM_001363118.2:c.851C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_001363118.2(SLC52A2):​c.851C>T​(p.Ala284Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A284D) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC52A2 NM_001363118.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.896
• Publications: 4 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-144360343-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 96702.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363118.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC52A2	NM_001363118.2	MANE Select	c.851C>T	p.Ala284Val	missense	Exon 3 of 5	NP_001350047.1
	SLC52A2	NM_001253815.2		c.851C>T	p.Ala284Val	missense	Exon 3 of 5	NP_001240744.1
	SLC52A2	NM_001253816.2		c.851C>T	p.Ala284Val	missense	Exon 3 of 5	NP_001240745.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC52A2	ENST00000643944.2	MANE Select	c.851C>T	p.Ala284Val	missense	Exon 3 of 5	ENSP00000496184.2
	SLC52A2	ENST00000329994.7	TSL:1	c.851C>T	p.Ala284Val	missense	Exon 3 of 5	ENSP00000333638.2
	SLC52A2	ENST00000402965.5	TSL:2	c.851C>T	p.Ala284Val	missense	Exon 3 of 5	ENSP00000385961.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1456362 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724678

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47982

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111974

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.43	N
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.90
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.29
Sift	Benign	0.075	T
Sift4G	Uncertain	0.043	D
Polyphen		0.52	P
Vest4		0.46
MutPred		0.76		Loss of glycosylation at T286 (P = 0.2101)
MVP		0.52
MPC		0.39
ClinPred		0.84	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.076
gMVP		0.66
Mutation Taster		=43/57	disease causing

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

Other links and lift over

dbSNP: rs398123067; hg19: chr8-145584003;