Genetic Variant SLC22A5:p.Pro46Ser (chr5-132370108-C-T) – ACMG Classification: Pathogenic (20 pts)

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3PM1PM5PP3_StrongPP5_Very_Strong

The NM_003060.4(SLC22A5):c.136C>T(p.Pro46Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000761 in 1,611,858 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000605131: Functional analyses of the variant protein show reduced transport to the cell membrane and substantially reduced carnitine transport activity (Filippo 2011, Frigeni 2017, Rose 2012)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P46L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00047 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00079 ( 1 hom. )

Consequence

SLC22A5
NM_003060.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:25

Conservation

PhyloP100: 7.28

Publications

42 publications found

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:

MIR3936HG (HGNC:40538): (MIR3936 host gene)

MIR3936HG links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 20 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000605131: Functional analyses of the variant protein show reduced transport to the cell membrane and substantially reduced carnitine transport activity (Filippo 2011, Frigeni 2017, Rose 2012).; SCV000632526: Experimental studies have shown that this missense change affects SLC22A5 function (PMID: 17126586, 21126579).; SCV000698144: "These in silico predictions are confirmed via multiple functional studies, Rose_2012 and Filipp_2011, that indicate the variant to "impair glycosylation and maturation of OCTN2 transporters to the plasma membrane."" Rose_2012 and Filipp_2011; SCV000711452: "In vitro functional studies also provide evidence that the p.Pro46Ser variant may impact protein function (di San Filippo 2011)."; SCV000915111: "When expressed in CHO cells, the p.Pro46Ser variant protein had reduced carnitine transport compared to wild type and was largely retained in the cytoplasm rather than being found at the plasma membrane (Filippo et al. 2011)."; SCV000239178: "Carnitine transport was significantly decreased in both skin fibroblasts from patients harboring P46S and in CHO cells overexpressing P46S (Frigeni et al., 2017; Rose et al., 2012)"

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 18 uncertain in NM_003060.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-132370109-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 25357.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.962

PP5

Variant 5-132370108-C-T is Pathogenic according to our data. Variant chr5-132370108-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 193250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003060.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC22A5	NM_003060.4	MANE Select	c.136C>T	p.Pro46Ser	missense	Exon 1 of 10	NP_003051.1	O76082-1
SLC22A5	NM_001308122.2		c.136C>T	p.Pro46Ser	missense	Exon 1 of 11	NP_001295051.1	O76082-3
MIR3936HG	NR_110997.1		n.-192G>A		upstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC22A5	ENST00000245407.8	TSL:1 MANE Select	c.136C>T	p.Pro46Ser	missense	Exon 1 of 10	ENSP00000245407.3	O76082-1
SLC22A5	ENST00000435065.7	TSL:1	c.136C>T	p.Pro46Ser	missense	Exon 1 of 11	ENSP00000402760.2	O76082-3
SLC22A5	ENST00000448810.6	TSL:1	n.136C>T		non_coding_transcript_exon	Exon 1 of 10	ENSP00000401860.2	H7C1R8

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000882

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000446

AC:

109

AN:

244204

AF XY:

0.000413

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000584

Gnomad ASJ exome

AF:

0.000605

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000956

Gnomad NFE exome

AF:

0.000886

Gnomad OTH exome

AF:

0.000338

GnomAD4 exome

AF:

0.000791

AC:

1154

AN:

1459644

Hom.:

Cov.:

AF XY:

0.000724

AC XY:

526

AN XY:

726162

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33446

American (AMR)

AF:

0.0000673

AC:

AN:

44594

Ashkenazi Jewish (ASJ)

AF:

0.000767

AC:

AN:

26082

East Asian (EAS)

AF:

0.00

AC:

AN:

39642

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86160

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000997

AC:

1108

AN:

1111368

Other (OTH)

AF:

0.000266

AC:

AN:

60250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

149

223

298

372

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000473

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41472

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000882

AC:

AN:

68014

Other (OTH)

AF:

0.000957

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000788

Hom.:

Bravo

AF:

0.000453

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000454

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Renal carnitine transport defect (15)

not provided (9)

See cases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

PhyloP100

7.3

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-7.1

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.96

MVP

1.0

MPC

0.81

ClinPred

0.91

GERP RS

5.3

PromoterAI

-0.0075

Neutral

(source)

Varity_R

0.86

gMVP

0.96

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over