chr11-22272895-C-G
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting
The NM_213599.3(ANO5):āc.2141C>Gā(p.Thr714Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000787 in 1,614,064 control chromosomes in the GnomAD database, including 4 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_213599.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000901 AC: 137AN: 152122Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000887 AC: 223AN: 251442Hom.: 1 AF XY: 0.000905 AC XY: 123AN XY: 135890
GnomAD4 exome AF: 0.000776 AC: 1134AN: 1461824Hom.: 4 Cov.: 32 AF XY: 0.000803 AC XY: 584AN XY: 727222
GnomAD4 genome AF: 0.000900 AC: 137AN: 152240Hom.: 0 Cov.: 32 AF XY: 0.000806 AC XY: 60AN XY: 74438
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:6
Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -
PM3, PS4_moderate -
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The ANO5 c.2141C>G; p.Thr714Ser variant (rs200631556) is reported in the literature in multiple individuals affected with limb girdle muscular dystrophy and unspecified neuromuscular disorders; however, it is only rarely found with a second pathogenic ANO5 variant (Gonzalez-Quereda 2020, Nallamilli 2018, Savarese 2015). This variant is also reported in ClinVar (Variation ID: 195004) and is found in the general population with an overall allele frequency of 0.09% (250/282,842 alleles, including 1 homozygote) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.498). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Gonzalez-Quereda L et al. Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain. Genes (Basel). 2020 May 11;11(5):539. PMID: 32403337. Nallamilli BRR et al. Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients. Ann Clin Transl Neurol. 2018 Dec 1;5(12):1574-1587. PMID: 30564623. Savarese M et al. Next generation sequencing on patients with LGMD and nonspecific myopathies: Findings associated with ANO5 mutations. Neuromuscul Disord. 2015 Jul;25(7):533-41. PMID: 25891276. -
ANO5: PM3:Strong, PM2 -
Reported previously in individuals with muscular dystrophy, suspected LGMD, and/or unspecified neuromuscular disorder with myopathic changes on biopsy who harbored another ANO5 pathogenic variant; however, segregation analysis was not provided and functional characterization of the variant was not performed (PMID: 22402862, 30564623, 32403337); Reported previously in individuals with limb-girdle muscular dystrophy, suspected limb-girdle muscular dystrophy, and Miyoshi myopathy who were heterozygous for this change and did not have another identifiable ANO5 pathogenic variant; however, additional clinical information was not provided and functional characterization of the variant was not completed (PMID: 25891276, 30564623, 36352632); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23047743, 34426522, 33023636, 30564623, 32403337, 22402862, 25891276, Schiava2022[casereport], 36913258, 35239206, 27884173, 36352632, 37526466) -
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ANO5-Related Muscle Diseases Uncertain:1
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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Gnathodiaphyseal dysplasia Uncertain:1
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Autosomal recessive limb-girdle muscular dystrophy type 2L Uncertain:1
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Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at