rs11568525

Positions:

chr5-132394243-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003060.4(SLC22A5):c.1645C>T(p.Pro549Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00382 in 1,612,766 control chromosomes in the GnomAD database, including 215 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 122 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 93 hom. )

Consequence

SLC22A5
NM_003060.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.76

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:

SLC22A5 (HGNC:):

SLC22A5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022649765).

BP6

Variant 5-132394243-C-T is Benign according to our data. Variant chr5-132394243-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 25432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132394243-C-T is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC22A5	NM_003060.4 linkuse as main transcript	c.1645C>T	p.Pro549Ser	missense_variant	10/10	ENST00000245407.8	NP_003051.1	O76082-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC22A5	ENST00000245407.8 linkuse as main transcript	c.1645C>T	p.Pro549Ser	missense_variant	10/10	1	NM_003060.4	ENSP00000245407.3		O76082-1

Frequencies

GnomAD3 genomes

AF:

0.0215

AC:

3267

AN:

152206

Hom.:

122

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0755

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00596

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.0129

GnomAD3 exomes

AF:

0.00539

AC:

1356

AN:

251468

Hom.:

AF XY:

0.00400

AC XY:

544

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.0757

Gnomad AMR exome

AF:

0.00298

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:

0.0000967

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00198

AC:

2886

AN:

1460442

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

1231

AN XY:

726638

show subpopulations

Gnomad4 AFR exome

AF:

0.0734

Gnomad4 AMR exome

AF:

0.00342

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000414

Gnomad4 OTH exome

AF:

0.00361

GnomAD4 genome

AF:

0.0215

AC:

3268

AN:

152324

Hom.:

122

Cov.:

AF XY:

0.0209

AC XY:

1557

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0753

Gnomad4 AMR

AF:

0.00595

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.00381

Hom.:

Bravo

AF:

0.0246

ESP6500AA

AF:

0.0697

AC:

307

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00650

AC:

789

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Renal carnitine transport defect

Benign:6

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely benign, criteria provided, single submitter	in vitro;research	Giacomini Lab, University of California, San Francisco	Oct 03, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 12, 2018	Variant summary: SLC22A5 c.1645C>T (p.Pro549Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0072 in 277216 control chromosomes in the gnomAD database, including 83 homozygotes. The observed variant frequency is approximately 2-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency phenotype (0.0046), strongly suggesting that the variant is benign. c.1645C>T has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency . These report(s) do not provide unequivocal conclusions about association of the variant with Systemic Primary Carnitine Deficiency . Multiple functional studies, Amat di San Filippo_2008, Frigeni_2017, Urban_2006, found the variant to act comparable to wild type function. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -

SLC22A5-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2020

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

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.66

T;T

MetaRNN

Benign

0.0023

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;.

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.079

Sift

Benign

0.086

T;T

Sift4G

Benign

0.27

T;T

Polyphen

0.0

B;.

Vest4

0.12

MVP

0.81

MPC

0.21

ClinPred

0.0081

GERP RS

4.4

Varity_R

0.035

gMVP

0.43

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