5-132378408-G-T

Position:

chr5-132378408-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_003060.4(SLC22A5):c.424G>T(p.Ala142Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000249 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

SLC22A5
NM_003060.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10U:1

Conservation

PhyloP100: 0.875

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-132378408-G-T is Pathogenic according to our data. Variant chr5-132378408-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 25372.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=6, Likely_pathogenic=3}. Variant chr5-132378408-G-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.099416435). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC22A5	NM_003060.4 linkuse as main transcript	c.424G>T	p.Ala142Ser	missense_variant	2/10	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.424G>T	p.Ala142Ser	missense_variant	2/10	1	NM_003060.4	ENSP00000245407.3		O76082-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251494

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

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:

0.000163

GnomAD4 exome

AF:

0.000267

AC:

391

AN:

1461866

Hom.:

Cov.:

AF XY:

0.000263

AC XY:

191

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000335

Gnomad4 OTH exome

AF:

0.000281

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000118

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Renal carnitine transport defect

Pathogenic:8

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 15, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 142 of the SLC22A5 protein (p.Ala142Ser). This variant is present in population databases (rs151231558, gnomAD 0.009%). This missense change has been observed in individual(s) with carnitine deficiency (PMID: 20574985, 21922592). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 25372). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC22A5 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect SLC22A5 function (PMID: 2216472, 16652335, 21922592). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 07, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 07, 2017	The p.Ala142Ser (NM_003060.3 c.424G>T) variant in SLC22A5 (previously referred t o as OCTN2) has been reported in at least 1 homozygous and 9 compound heterozygo us individuals with primary carnitine deficiency or asymptomatic mothers of pati ents identified in NBS (Amat di San Filippo 2006, Li 2010, Mazzini 2011, Rose 2 012).This variant has been identified in 0.009% (12/126,728) of European chromos omes by the Genome Aggregation Database (gnomAD, http://gnomAD.broadinstitute.or g; dbSNP rs151231558). Although this variant has been seen in the general popula tion, its frequency is low enough to be consistent with a recessive carrier freq uency. In summary, although additional studies are required to fully establish i ts clinical significance, the p.Ala142Thr variant is likely pathogenic for prima ry carnitine deficiency in an autosomal recessive manner based upon its occurren ce in individuals with this disease. -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Oct 21, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 24, 2021	Variant summary: SLC22A5 c.424G>T (p.Ala142Ser) results in a conservative amino acid change located in the Major facilitator superfamily domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251494 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (5.6e-05 vs 0.0046), allowing no conclusion about variant significance. c.424G>T has been reported in the literature in multiple individuals affected with Systemic Primary Carnitine Deficiency, in most cases with p.R488H in cis, along with a second pathogenic variant on the second allele (Amat di San Filippo_2006, Frigeni_2017, Gallant_2017, Mazzini_2011, Thompson_2018). Two publications, one of which is a large study of 143 patients evaluated for Systemic Primary Carnitine Deficiency, reports this variant (p.A142S) in isolation along with a second pathogenic allele in trans (Li_2010, El-Hattab_2010). A functional study showed that the carnitine transport was markedly impaired when both mutations were combined within the same cDNA, however, none of the two missense mutations impaired carnitine transport when expressed alone in CHO cells (Amat di San Filippo_2006). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=3) and likely pathogenic (n=2). Based on this evidence, the variant is classified as pathogenic both in isolation as well as when observed as a complex allele in cis with p.R488H. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jun 12, 2017	- -

not provided

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 28, 2024	PM2, PM3_very_strong, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 30, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.080

T;.;.

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.061

LIST_S2

Benign

0.78

T;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.099

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.5

L;.;.

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.80

N;N;N

REVEL

Uncertain

0.41

Sift

Benign

0.20

T;T;T

Sift4G

Benign

0.73

T;T;T

Polyphen

0.0080

B;.;.

Vest4

0.36

MVP

0.80

MPC

0.21

ClinPred

0.025

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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