rs4577050
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_001365088.1(SLC12A6):c.3003C>T(p.Leu1001=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.667 in 1,607,134 control chromosomes in the GnomAD database, including 360,633 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.61 ( 29337 hom., cov: 32)
Exomes 𝑓: 0.67 ( 331296 hom. )
Consequence
SLC12A6
NM_001365088.1 synonymous
NM_001365088.1 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.156
Genes affected
SLC12A6 (HGNC:10914): (solute carrier family 12 member 6) This gene is a member of the K-Cl cotransporter (KCC) family. K-Cl cotransporters are integral membrane proteins that lower intracellular chloride concentrations below the electrochemical equilibrium potential. The proteins encoded by this gene are activated by cell swelling induced by hypotonic conditions. Alternate splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are associated with agenesis of the corpus callosum with peripheral neuropathy. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.59).
BP6
?
Variant 15-34236747-G-A is Benign according to our data. Variant chr15-34236747-G-A is described in ClinVar as [Benign]. Clinvar id is 159896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-34236747-G-A is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=0.156 with no splicing effect.
BA1
?
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC12A6 | NM_001365088.1 | c.3003C>T | p.Leu1001= | synonymous_variant | 23/26 | ENST00000354181.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC12A6 | ENST00000354181.8 | c.3003C>T | p.Leu1001= | synonymous_variant | 23/26 | 1 | NM_001365088.1 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.611 AC: 92826AN: 151918Hom.: 29338 Cov.: 32
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GnomAD3 exomes AF: 0.658 AC: 165521AN: 251420Hom.: 55282 AF XY: 0.660 AC XY: 89611AN XY: 135876
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GnomAD4 exome AF: 0.673 AC: 978619AN: 1455098Hom.: 331296 Cov.: 32 AF XY: 0.671 AC XY: 485974AN XY: 724248
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GnomAD4 genome ? AF: 0.611 AC: 92866AN: 152036Hom.: 29337 Cov.: 32 AF XY: 0.614 AC XY: 45631AN XY: 74306
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ClinVar
Significance: Benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Agenesis of the corpus callosum with peripheral neuropathy Benign:4
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 10, 2021 | - - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not specified Benign:3
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 06, 2017 | Variant summary: The SLC12A6 c.3003C>T (p.Leu1001Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. This variant was found in 79011/121370 control chromosomes (26234 homozygotes) at a frequency of 0.6509928, which is approximately 26 times the estimated maximal expected allele frequency of a pathogenic SLC12A6 variant (0.025), strong evidence that this variant is a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at