rs144290224

chr8-144360710-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_001363118.2(SLC52A2):c.1122C>T(p.Leu374=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000636 in 1,565,694 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (2 hom.)
• Consequence: SLC52A2 NM_001363118.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.657

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 8-144360710-C-T is Benign according to our data. Variant chr8-144360710-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 392275.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=6}. Variant chr8-144360710-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.657 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000663 (96/144896) while in subpopulation NFE AF= 0.00116 (77/66244). AF 95% confidence interval is 0.000953. There are 0 homozygotes in gnomad4. There are 45 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC52A2	NM_001363118.2	c.1122C>T	p.Leu374=	synonymous_variant	4/5	ENST00000643944.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC52A2	ENST00000643944.2	c.1122C>T	p.Leu374=	synonymous_variant	4/5		NM_001363118.2	P1

Frequencies

GnomAD3 genomes AF: 0.000663 AC: 96 AN: 144896 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000414

Gnomad ASJ AF: 0.000293

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000222

Gnomad FIN AF: 0.000530

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000657 AC: 157 AN: 238862 Hom.: 0 AF XY: 0.000607 AC XY: 79 AN XY: 130054

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.000106

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000677

Gnomad FIN exome AF: 0.000999

Gnomad NFE exome AF: 0.00119

Gnomad OTH exome AF: 0.000511

GnomAD4 exome AF: 0.000633 AC: 899 AN: 1420798 Hom.: 2 Cov.: 42 AF XY: 0.000665 AC XY: 469 AN XY: 705776

Gnomad4 AFR exome AF: 0.0000304

Gnomad4 AMR exome AF: 0.000136

Gnomad4 ASJ exome AF: 0.000197

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000589

Gnomad4 FIN exome AF: 0.00107

Gnomad4 NFE exome AF: 0.000737

Gnomad4 OTH exome AF: 0.000561

GnomAD4 genome AF: 0.000663 AC: 96 AN: 144896 Hom.: 0 Cov.: 33 AF XY: 0.000639 AC XY: 45 AN XY: 70406

Gnomad4 AFR AF: 0.000155

Gnomad4 AMR AF: 0.000414

Gnomad4 ASJ AF: 0.000293

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000222

Gnomad4 FIN AF: 0.000530

Gnomad4 NFE AF: 0.00116

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00138 Hom.: 0

Bravo AF: 0.000548

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Sep 27, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	SLC52A2: BP4 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 23, 2017

p.Leu374Leu in exon 4 of SLC52A2: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 0.12% (76/63972) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs144290224). -

Brown-Vialetto-van Laere syndrome 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

SLC52A2-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 14, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	7.3
Dann	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs144290224; hg19: chr8-145584370; COSMIC: COSV57352443; COSMIC: COSV57352443;