dbSNP rs72552734: SLC22A5:p.Glu452Lys (chr5-132392519-G-A) – ACMG Classification: Pathogenic (13 pts)

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3PM1PM2PP3_StrongPP5

The NM_003060.4(SLC22A5):c.1354G>A(p.Glu452Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000817118: Experimental studies have shown that this missense change affects SLC22A5 function (PMID:10679939)." and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

SLC22A5
NM_003060.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:1

Conservation

PhyloP100: 9.57

Publications

17 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 Gene-Disease associations (from GenCC):

systemic primary carnitine deficiency disease
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet, G2P, ClinGen
short QT syndrome
Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

SLC22A5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000817118: Experimental studies have shown that this missense change affects SLC22A5 function (PMID: 10679939).; SCV001431936: Several publications report experimental evidence evaluating an impact on protein function (example Frigeni_2017, Wang_2000).; SCV005201204: Published functional studies demonstrate 24% of wild type transporter (PMID: 10679939)

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_003060.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

PP5

Variant 5-132392519-G-A is Pathogenic according to our data. Variant chr5-132392519-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 25421.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC22A5	NM_003060.4	MANE Select	c.1354G>A	p.Glu452Lys	missense	Exon 8 of 10	NP_003051.1	O76082-1
	SLC22A5	NM_001308122.2		c.1426G>A	p.Glu476Lys	missense	Exon 9 of 11	NP_001295051.1	O76082-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC22A5	ENST00000245407.8	TSL:1 MANE Select	c.1354G>A	p.Glu452Lys	missense	Exon 8 of 10	ENSP00000245407.3	O76082-1
SLC22A5	ENST00000435065.7	TSL:1	c.1426G>A	p.Glu476Lys	missense	Exon 9 of 11	ENSP00000402760.2	O76082-3
SLC22A5	ENST00000448810.6	TSL:1	n.*206G>A		non_coding_transcript_exon	Exon 8 of 10	ENSP00000401860.2	H7C1R8

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000278

AC:

AN:

251480

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1461754

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000324

AC:

AN:

1111876

Other (OTH)

AF:

0.0000331

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41406

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

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:

0.0000258

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Renal carnitine transport defect (7)

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.3

PhyloP100

9.6

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

1.0

MutPred

0.92

Gain of methylation at E452 (P = 0.0203)

MVP

1.0

MPC

0.86

ClinPred

1.0

GERP RS

6.2

Varity_R

0.98

gMVP

0.96

Mutation Taster

=6/94

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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