5-132370222-T-TACCGGCTCGCC
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_003060.4(SLC22A5):c.254_264dupGGCTCGCCACC(p.Ile89GlyfsTer45) variant causes a frameshift change. The variant allele was found at a frequency of 0.000046 in 152,192 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000020 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
SLC22A5
NM_003060.4 frameshift
NM_003060.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.47
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 5-132370222-T-TACCGGCTCGCC is Pathogenic according to our data. Variant chr5-132370222-T-TACCGGCTCGCC is described in ClinVar as [Pathogenic]. Clinvar id is 38790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152192Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000375 AC: 7AN: 186880Hom.: 0 AF XY: 0.0000292 AC XY: 3AN XY: 102696
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000203 AC: 29AN: 1427734Hom.: 0 Cov.: 31 AF XY: 0.0000198 AC XY: 14AN XY: 707348
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152192Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74354
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Renal carnitine transport defect Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 05, 2024 | This sequence change creates a premature translational stop signal (p.Ile89Glyfs*45) 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). This variant is present in population databases (rs757431170, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with primary carnitine deficiency (PMID: 11715001, 28841266). ClinVar contains an entry for this variant (Variation ID: 38790). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 04, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 26, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 04, 2016 | Variant summary: The SLC22A5 c.254_264dup11 (p.Ile89Glyfs) variant results in a premature termination codon, predicted to cause a truncated or absent SLC22A5 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant is absent in 42704 control chromosomes. This variant has been reported in multiple PCD patients both homozygously and heterozygously. Functional study showed this variant caused decreased levels of mature mRNA. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 16, 2024 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 27, 2023 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 16652335, 31980526, 11715001, 21922592, 23379544, 28841266, 15714519) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2020 | - - |
Decreased circulating carnitine concentration Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 26, 2020 | - - |
Congenital myasthenic syndrome 20 Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Ricardo Maselli Laboratory, University of California Davis | Jan 16, 2024 | Congenital Myasthenic Syndrome with episodic apneas. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at