NM_001363118.2:c.1001+6C>T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 [Likely_benign]. Clinvar id is 540439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144360499-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC52A2	NM_001363118.2	c.1001+6C>T		splice_region_variant, intron_variant	Intron 3 of 4	ENST00000643944.2	NP_001350047.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC52A2	ENST00000643944.2	c.1001+6C>T		splice_region_variant, intron_variant	Intron 3 of 4		NM_001363118.2	ENSP00000496184.2

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

GnomAD3 exomes AF: 0.000860 AC: 203 AN: 236120 Hom.: 3 AF XY: 0.000668 AC XY: 86 AN XY: 128734

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 SAS 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

Gnomad4 AFR exome AF: 0.0104

Gnomad4 AMR exome AF: 0.000858

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000350

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000977

Gnomad4 OTH exome AF: 0.000887

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

Gnomad4 AFR AF: 0.00966

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000600 Hom.: 0

Bravo AF: 0.00357

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SLC52A2: BP4, BS2 -

Feb 11, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brown-Vialetto-van Laere syndrome 2 Benign:1

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.2
DANN	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs139398461; hg19: chr8-145584159;