rs117500243

Variant names:

• chr8-144359845-C-A
• rs117500243
• NM_001363118.2:c.353C>A

Your query was ambiguous. Multiple possible variants found:

• chr8-144359845-C-A
• chr8-144359845-C-T
• chr8-144359845-C-G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001363118.2(SLC52A2):​c.353C>A​(p.Ala118Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00397 in 1,613,714 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A118P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (20 hom.)
• Consequence: SLC52A2 NM_001363118.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:11
• Conservation: PhyloP100: 3.85
• Publications: 13 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, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_001363118.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.012701243).
• BP6: Variant 8-144359845-C-A is Benign according to our data. Variant chr8-144359845-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 372996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00282 (429/152322) while in subpopulation NFE AF = 0.00462 (314/68024). AF 95% confidence interval is 0.0042. There are 2 homozygotes in GnomAd4. There are 190 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.353C>A	p.Ala118Asp	missense	Exon 3 of 5	NP_001350047.1	Q9HAB3
	SLC52A2	NM_001253815.2		c.353C>A	p.Ala118Asp	missense	Exon 3 of 5	NP_001240744.1	Q9HAB3
	SLC52A2	NM_001253816.2		c.353C>A	p.Ala118Asp	missense	Exon 3 of 5	NP_001240745.1	Q9HAB3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC52A2	ENST00000643944.2	MANE Select	c.353C>A	p.Ala118Asp	missense	Exon 3 of 5	ENSP00000496184.2	Q9HAB3
	SLC52A2	ENST00000329994.7	TSL:1	c.353C>A	p.Ala118Asp	missense	Exon 3 of 5	ENSP00000333638.2	Q9HAB3
	SLC52A2	ENST00000402965.5	TSL:2	c.353C>A	p.Ala118Asp	missense	Exon 3 of 5	ENSP00000385961.1	Q9HAB3

Frequencies

GnomAD3 genomes AF: 0.00282 AC: 429 AN: 152204 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00462

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00274 AC: 689 AN: 251100 AF XY: 0.00278

Gnomad AFR exome AF: 0.000555

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00914

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00440

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00409 AC: 5979 AN: 1461392 Hom.: 20 Cov.: 31 AF XY: 0.00394 AC XY: 2863 AN XY: 726992

African (AFR) AF: 0.000926 AC: 31 AN: 33480

American (AMR) AF: 0.00143 AC: 64 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00953 AC: 249 AN: 26136

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

South Asian (SAS) AF: 0.000835 AC: 72 AN: 86258

European-Finnish (FIN) AF: 0.000359 AC: 19 AN: 52944

Middle Eastern (MID) AF: 0.00728 AC: 42 AN: 5768

European-Non Finnish (NFE) AF: 0.00474 AC: 5272 AN: 1111998

Other (OTH) AF: 0.00381 AC: 230 AN: 60386

GnomAD4 genome AF: 0.00282 AC: 429 AN: 152322 Hom.: 2 Cov.: 33 AF XY: 0.00255 AC XY: 190 AN XY: 74464

African (AFR) AF: 0.000698 AC: 29 AN: 41568

American (AMR) AF: 0.000719 AC: 11 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00462 AC: 314 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00386 Hom.: 2

Bravo AF: 0.00280

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00285 AC: 346

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00458

EpiControl AF: 0.00474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	Brown-Vialetto-van Laere syndrome 2 (3)
-	1	1	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	SLC52A2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.081
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.099	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.9
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.49
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.020	D
Polyphen		0.81	P
Vest4		0.60
MVP		0.62
MPC		0.30
ClinPred		0.028	T
GERP RS		3.5
Varity_R		0.30
gMVP		0.87
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs117500243; hg19: chr8-145583505; COSMIC: COSV57351405; COSMIC: COSV57351405;