rs274558

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003060.4(SLC22A5):c.807A>G(p.Leu269=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 1,613,282 control chromosomes in the GnomAD database, including 137,840 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L269L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.41 ( 13083 hom., cov: 33)

Exomes 𝑓: 0.40 ( 124757 hom. )

Consequence

SLC22A5
NM_003060.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.264

Variant links:

Genes affected

SLC22A5 (HGNC:10969): (solute carrier family 22 member 5) Polyspecific organic cation transporters in the liver, kidney, intestine, and other organs are critical for elimination of many endogenous small organic cations as well as a wide array of drugs and environmental toxins. The encoded protein is a plasma integral membrane protein which functions both as an organic cation transporter and as a sodium-dependent high affinity carnitine transporter. The encoded protein is involved in the active cellular uptake of carnitine. Mutations in this gene are the cause of systemic primary carnitine deficiency (CDSP), an autosomal recessive disorder manifested early in life by hypoketotic hypoglycemia and acute metabolic decompensation, and later in life by skeletal myopathy or cardiomyopathy. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2015]

SLC22A5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 5-132385482-A-G is Benign according to our data. Variant chr5-132385482-A-G is described in ClinVar as [Benign]. Clinvar id is 94101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132385482-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.264 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.651 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC22A5	NM_003060.4 linkuse as main transcript	c.807A>G	p.Leu269=	synonymous_variant	4/10	ENST00000245407.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC22A5	ENST00000245407.8 linkuse as main transcript	c.807A>G	p.Leu269=	synonymous_variant	4/10	1	NM_003060.4	P1	O76082-1

Frequencies

GnomAD3 genomes

AF:

0.406

AC:

61672

AN:

151926

Hom.:

13075

Cov.:

show subpopulations

Gnomad AFR

AF:

0.359

Gnomad AMI

AF:

0.239

Gnomad AMR

AF:

0.352

Gnomad ASJ

AF:

0.416

Gnomad EAS

AF:

0.670

Gnomad SAS

AF:

0.640

Gnomad FIN

AF:

0.512

Gnomad MID

AF:

0.491

Gnomad NFE

AF:

0.395

Gnomad OTH

AF:

0.391

GnomAD3 exomes

AF:

0.435

AC:

109359

AN:

251282

Hom.:

25387

AF XY:

0.448

AC XY:

60802

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.357

Gnomad AMR exome

AF:

0.316

Gnomad ASJ exome

AF:

0.402

Gnomad EAS exome

AF:

0.643

Gnomad SAS exome

AF:

0.627

Gnomad FIN exome

AF:

0.509

Gnomad NFE exome

AF:

0.387

Gnomad OTH exome

AF:

0.421

GnomAD4 exome

AF:

0.404

AC:

591038

AN:

1461238

Hom.:

124757

Cov.:

AF XY:

0.412

AC XY:

299529

AN XY:

726990

show subpopulations

Gnomad4 AFR exome

AF:

0.354

Gnomad4 AMR exome

AF:

0.325

Gnomad4 ASJ exome

AF:

0.400

Gnomad4 EAS exome

AF:

0.668

Gnomad4 SAS exome

AF:

0.621

Gnomad4 FIN exome

AF:

0.505

Gnomad4 NFE exome

AF:

0.377

Gnomad4 OTH exome

AF:

0.416

GnomAD4 genome

AF:

0.406

AC:

61712

AN:

152044

Hom.:

13083

Cov.:

AF XY:

0.417

AC XY:

30987

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.359

Gnomad4 AMR

AF:

0.352

Gnomad4 ASJ

AF:

0.416

Gnomad4 EAS

AF:

0.670

Gnomad4 SAS

AF:

0.642

Gnomad4 FIN

AF:

0.512

Gnomad4 NFE

AF:

0.395

Gnomad4 OTH

AF:

0.391

Alfa

AF:

0.385

Hom.:

17934

Bravo

AF:

0.385

Asia WGS

AF:

0.617

AC:

2144

AN:

3478

EpiCase

AF:

0.385

EpiControl

AF:

0.376

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Renal carnitine transport defect

Benign:7

Benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 07, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 18, 2016	Variant summary: The c.807A>G variant affects a non-conserved nucleotide, resulting in synonymous amino acid change. Mutatation Taster predicts polymorphism outcome for this variant. 5/5 splice-site tools via Alamut predict that this variant does not affect the consensus splice donor site though it may create a cryptic splice donor site as predicted by 3/5 tools. However, in silico prediction results are not definite and there are no functional studies to confirm this. This variant is found in 53257/121244 control chromosomes (12476 homozygotes) from the large and broad populations of ExAC at a frequency of 0.4392547, which is about 96 times greater than the maximal expected frequency of a pathogenic allele (0.0045644) in this gene. Thus this variant is a common polymorphism found in general population. In one family, this variant was found in cis with a potentially pathogenic variant p.Leu476Arg in homozygous state in two affected siblings and was found in homozygous state in the unaffected father of the siblings (Mutlu-Albayrak_2015) -- an evidence of lack of cosegregation which further supports the benign outcome. One clinical laboratory has classified this variant as benign. Taken together, this variant has been classified as Benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

Cadd

Benign

7.1

Dann

Benign

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over