5-132390838-T-TA
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_003060.4(SLC22A5):c.1202dup(p.Tyr401Ter) variant causes a stop gained, frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000028 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.000028 ( 0 hom. )
Consequence
SLC22A5
NM_003060.4 stop_gained, frameshift
NM_003060.4 stop_gained, frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.73
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 5-132390838-T-TA is Pathogenic according to our data. Variant chr5-132390838-T-TA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC22A5 | NM_003060.4 | c.1202dup | p.Tyr401Ter | stop_gained, frameshift_variant | 7/10 | ENST00000245407.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC22A5 | ENST00000245407.8 | c.1202dup | p.Tyr401Ter | stop_gained, frameshift_variant | 7/10 | 1 | NM_003060.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251478Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135914
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GnomAD4 exome AF: 0.0000280 AC: 41AN: 1461892Hom.: 0 Cov.: 31 AF XY: 0.0000371 AC XY: 27AN XY: 727248
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Renal carnitine transport defect Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 14, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6417). This premature translational stop signal has been observed in individual(s) with primary carnitine deficiency (PMID: 10051646, 12210323). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs768720460, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Tyr401*) in the SLC22A5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC22A5 are known to be pathogenic (PMID: 9916797). - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Oct 26, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 02, 1999 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 07, 2020 | - - |
Decreased circulating carnitine concentration Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 07, 2020 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 21, 2013 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at