chr8-144360499-C-T

Variant names:

• chr8-144360499-C-T
• rs139398461
• NM_001363118.2:c.1001+6C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001363118.2(SLC52A2):​c.1001+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000623 in 1,591,752 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (1 hom.)
• Consequence: SLC52A2 NM_001363118.2 splice_region, intron
• Scores: Splicing: ADA: 0.00007872
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0490
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 8-144360499-C-T is Benign according to our data. Variant chr8-144360499-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 540439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00287 (437/152392) while in subpopulation AFR AF = 0.00966 (402/41602). AF 95% confidence interval is 0.00888. There are 3 homozygotes in GnomAd4. There are 202 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.1001+6C>T		splice_region intron	N/A	NP_001350047.1	Q9HAB3
	SLC52A2	NM_001253815.2		c.1001+6C>T		splice_region intron	N/A	NP_001240744.1	Q9HAB3
	SLC52A2	NM_001253816.2		c.1001+6C>T		splice_region intron	N/A	NP_001240745.1	Q9HAB3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC52A2	ENST00000643944.2	MANE Select	c.1001+6C>T		splice_region intron	N/A	ENSP00000496184.2	Q9HAB3
	SLC52A2	ENST00000329994.7	TSL:1	c.1001+6C>T		splice_region intron	N/A	ENSP00000333638.2	Q9HAB3
	SLC52A2	ENST00000402965.5	TSL:2	c.1001+6C>T		splice_region intron	N/A	ENSP00000385961.1	Q9HAB3

Frequencies

GnomAD3 genomes AF: 0.00288 AC: 438 AN: 152274 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00972

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000860 AC: 203 AN: 236120 AF XY: 0.000668

Gnomad AFR exome AF: 0.00996

Gnomad AMR exome AF: 0.000881

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000730

Gnomad OTH exome AF: 0.000845

GnomAD4 exome AF: 0.000386 AC: 555 AN: 1439360 Hom.: 1 Cov.: 30 AF XY: 0.000348 AC XY: 249 AN XY: 714952

African (AFR) AF: 0.0104 AC: 346 AN: 33278

American (AMR) AF: 0.000858 AC: 38 AN: 44306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25592

East Asian (EAS) AF: 0.00 AC: 0 AN: 39486

South Asian (SAS) AF: 0.0000350 AC: 3 AN: 85594

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40392

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5734

European-Non Finnish (NFE) AF: 0.0000977 AC: 108 AN: 1105216

Other (OTH) AF: 0.000887 AC: 53 AN: 59762

GnomAD4 genome AF: 0.00287 AC: 437 AN: 152392 Hom.: 3 Cov.: 33 AF XY: 0.00271 AC XY: 202 AN XY: 74526

African (AFR) AF: 0.00966 AC: 402 AN: 41602

American (AMR) AF: 0.00137 AC: 21 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68042

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.000600 Hom.: 0

Bravo AF: 0.00357

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Brown-Vialetto-van Laere syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.2
DANN	Benign	0.57
PhyloP100		0.049
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000079
dbscSNV1_RF	Benign	0.010
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: rs139398461; hg19: chr8-145584159;