chr8-144360343-C-A

Position:

• chr8-144360343-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001363118.2(SLC52A2):​c.851C>A​(p.Ala284Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC52A2 NM_001363118.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 0.896

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916
• PP5: Variant 8-144360343-C-A is Pathogenic according to our data. Variant chr8-144360343-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 96702.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-144360343-C-A is described in UniProt as null. Variant chr8-144360343-C-A is described in UniProt as null. Variant chr8-144360343-C-A is described in UniProt as null. Variant chr8-144360343-C-A is described in UniProt as null. Variant chr8-144360343-C-A is described in UniProt as null. Variant chr8-144360343-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC52A2	NM_001363118.2	c.851C>A	p.Ala284Asp	missense_variant	3/5	ENST00000643944.2	NP_001350047.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC52A2	ENST00000643944.2	c.851C>A	p.Ala284Asp	missense_variant	3/5		NM_001363118.2	ENSP00000496184	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Brown-Vialetto-van Laere syndrome 2 Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;D;.;D;D;D;D
Eigen	Benign	-0.018
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.48	N
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.067	T
MutationAssessor	Pathogenic	3.0	M;M;.;M;M;M;M
MutationTaster	Benign	1.0	D;N;N;N;N;N;N
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-4.0	D;D;D;D;D;D;.
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0020	D;D;D;D;D;D;.
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;.
Polyphen		0.88	P;P;.;P;P;P;P
Vest4		0.91
MutPred		0.77		Loss of glycosylation at T286 (P = 0.0882);Loss of glycosylation at T286 (P = 0.0882);.;Loss of glycosylation at T286 (P = 0.0882);Loss of glycosylation at T286 (P = 0.0882);Loss of glycosylation at T286 (P = 0.0882);Loss of glycosylation at T286 (P = 0.0882);
MVP		0.60
MPC		0.62
ClinPred		0.98	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.81
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs398123067; hg19: chr8-145584003;