13-23330159-T-G
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_014363.6(SACS):c.13717A>C(p.Asn4573His) variant causes a missense change. The variant allele was found at a frequency of 0.00441 in 1,613,956 control chromosomes in the GnomAD database, including 21 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: 0.00326 AC: 497AN: 152222Hom.: 3 Cov.: 33
GnomAD3 exomes AF: 0.00318 AC: 799AN: 250932Hom.: 2 AF XY: 0.00316 AC XY: 428AN XY: 135630
GnomAD4 exome AF: 0.00453 AC: 6614AN: 1461616Hom.: 18 Cov.: 32 AF XY: 0.00442 AC XY: 3217AN XY: 727114
GnomAD4 genome AF: 0.00326 AC: 496AN: 152340Hom.: 3 Cov.: 33 AF XY: 0.00319 AC XY: 238AN XY: 74496
ClinVar
Submissions by phenotype
Charlevoix-Saguenay spastic ataxia Pathogenic:1Uncertain:2Benign:4
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
European Non-Finnish population allele frequency is 0.4833% (rs34382952, 655/128756 alleles, 2 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1 -
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not specified Benign:4
Variant summary: SACS c.13717A>C (p.Asn4573His) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0044 in 1613956 control chromosomes, predominantly at a frequency of 0.0054 within the Non-Finnish European subpopulation in the gnomAD database (v.4.1), including 20 homozygotes. This suggests the variant is likely a benign polymorphism. c.13717A>C has been reported in the literature, primarily in the heterozygous state and in settings of multigene panel testing, in individuals affected with ataxias and other movement disorders, without strong evidence for causality (e.g. Vermeer_2009, Fogel_2012, Morais_2017, Martinez-Rubio_2022, OGorman_2019). These reports do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22287014, 36233161, 28832565, 31519934, 19779133). ClinVar contains an entry for this variant (Variation ID: 193707). Based on the evidence outlined above, the variant was classified as likely benign -
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not provided Uncertain:1Benign:2
This variant is associated with the following publications: (PMID: 23280630, 22162184, 22287014, 19779133, 28832565) -
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SACS: BS2 -
Hereditary spastic paraplegia Uncertain:1Benign:1
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Spastic paraplegia Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at