chr13-23337095-G-T
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_014363.6(SACS):c.6781C>A(p.Leu2261Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00531 in 1,613,958 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_014363.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00475 AC: 722AN: 152130Hom.: 5 Cov.: 33
GnomAD3 exomes AF: 0.00477 AC: 1198AN: 250910Hom.: 7 AF XY: 0.00474 AC XY: 643AN XY: 135696
GnomAD4 exome AF: 0.00536 AC: 7841AN: 1461710Hom.: 23 Cov.: 37 AF XY: 0.00504 AC XY: 3667AN XY: 727156
GnomAD4 genome AF: 0.00474 AC: 722AN: 152248Hom.: 5 Cov.: 33 AF XY: 0.00576 AC XY: 429AN XY: 74440
ClinVar
Submissions by phenotype
Charlevoix-Saguenay spastic ataxia Uncertain:2Benign:4
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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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
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The p.Leu266Ile variant was identified in the proband in trans with the SACS p.Thr458Ile variant of uncertain significance. The p.Leu2261Ile variant was previously identified in the literature, in compound heterozygous state with the p.Ser527* variant in a male patient with juvenile onset motor neuropathy, ataxia, and spasticity; these variants were considered causative (Bansagi_2017_PMID:28251916). The p.Leu2261Ile variant was also identified in compound heterozygous form (with p.Ser527*) in two affected siblings with disease onset in their 40s; the variants were reported as confirmed pathogenic. Both siblings were affected by gait disturbance and cerebellar ataxia. In addition, one sibling (male) was positive for demyelinating sensorimotor neuropathy, and MRI indicated generalized atrophy. The other sibling (female) was observed to have jerky ocular pursuit and optic atrophy (Pyle_2015_PMID:25497598). The variant was identified in dbSNP (rs146722795) and ClinVar (Conflicting interpretations of pathogenicity. Uncertain significance [1], benign [2], likely benign [2]. Classified as Uncertain significance for ARSACS in 2016 by Ilumina, likely benign in 2014 by Genome Diagnostics Centre and University Medical Centre Utrecht for ARSACS, Benign for spastic paraplegia in 2017 by Erasmus Medical Centre, Benign in 2017 by Invitae, and Likely benign in 2017 by Athena Diagnostics) databases. The variant was identified in control databases in 1397 of 282308 chromosomes (8 homozygous) at a frequency of 0.004948 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 542 of 25098 chromosomes (freq: 0.0216), European (non-Finnish) in 792 of 128852 chromosomes (freq: 0.006147), Other in 27 of 7194 chromosomes (freq: 0.003753), African in 26 of 24834 chromosomes (freq: 0.001047), Latino in 10 of 35420 chromosomes (freq: 0.000282), but was not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The p.Leu266 residue is conserved in mammals and other organisms; computational analyses (MUT Assessor, SIFT, Polyphen 2, MT, FATHMM, DANN, MetaLR, Revel) predict a deleterious impact to the protein. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
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not provided Benign:3
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This variant is associated with the following publications: (PMID: 23280630, 19779133, 24457356, 28251916, 25497598) -
SACS: BS1, BS2 -
Spastic paraplegia Benign:1
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SACS-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Hereditary spastic paraplegia Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at