rs146292053

Variant names:

• chr8-144360677-G-A
• rs146292053
• NM_001363118.2:c.1089G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001363118.2(SLC52A2):​c.1089G>A​(p.Pro363Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0056 in 1,604,502 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (11 hom., cov: 33)
  • Exomes 𝑓: 0.0056 (56 hom.)
• Consequence: SLC52A2 NM_001363118.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -8.89
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 8-144360677-G-A is Benign according to our data. Variant chr8-144360677-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 385698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-8.89 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00576 (876/152088) while in subpopulation NFE AF = 0.0068 (462/67942). AF 95% confidence interval is 0.00629. There are 11 homozygotes in GnomAd4. There are 494 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.1089G>A	p.Pro363Pro	synonymous	Exon 4 of 5	NP_001350047.1	Q9HAB3
	SLC52A2	NM_001253815.2		c.1089G>A	p.Pro363Pro	synonymous	Exon 4 of 5	NP_001240744.1	Q9HAB3
	SLC52A2	NM_001253816.2		c.1089G>A	p.Pro363Pro	synonymous	Exon 4 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.1089G>A	p.Pro363Pro	synonymous	Exon 4 of 5	ENSP00000496184.2	Q9HAB3
	SLC52A2	ENST00000329994.7	TSL:1	c.1089G>A	p.Pro363Pro	synonymous	Exon 4 of 5	ENSP00000333638.2	Q9HAB3
	SLC52A2	ENST00000675787.1		c.1078G>A	p.Ala360Thr	missense	Exon 3 of 4	ENSP00000502189.1	A0A6Q8PGB9

Frequencies

GnomAD3 genomes AF: 0.00576 AC: 876 AN: 151972 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0327

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00680

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00579 AC: 1405 AN: 242682 AF XY: 0.00565

Gnomad AFR exome AF: 0.000633

Gnomad AMR exome AF: 0.00111

Gnomad ASJ exome AF: 0.000508

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.0349

Gnomad NFE exome AF: 0.00598

Gnomad OTH exome AF: 0.00619

GnomAD4 exome AF: 0.00558 AC: 8111 AN: 1452414 Hom.: 56 Cov.: 45 AF XY: 0.00553 AC XY: 3998 AN XY: 722708

African (AFR) AF: 0.000628 AC: 21 AN: 33464

American (AMR) AF: 0.00126 AC: 56 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.000500 AC: 13 AN: 26008

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39682

South Asian (SAS) AF: 0.00186 AC: 160 AN: 86122

European-Finnish (FIN) AF: 0.0316 AC: 1444 AN: 45646

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5756

European-Non Finnish (NFE) AF: 0.00547 AC: 6081 AN: 1110890

Other (OTH) AF: 0.00515 AC: 310 AN: 60230

GnomAD4 genome AF: 0.00576 AC: 876 AN: 152088 Hom.: 11 Cov.: 33 AF XY: 0.00664 AC XY: 494 AN XY: 74350

African (AFR) AF: 0.000602 AC: 25 AN: 41504

American (AMR) AF: 0.00157 AC: 24 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5146

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4822

European-Finnish (FIN) AF: 0.0327 AC: 347 AN: 10596

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

European-Non Finnish (NFE) AF: 0.00680 AC: 462 AN: 67942

Other (OTH) AF: 0.00427 AC: 9 AN: 2108

Alfa AF: 0.00641 Hom.: 4

Bravo AF: 0.00314

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00540

EpiControl AF: 0.00475

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Brown-Vialetto-van Laere syndrome 2 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.8
DANN	Benign	0.81
PhyloP100		-8.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs146292053; hg19: chr8-145584337; COSMIC: COSV57351787; COSMIC: COSV57351787;