6-152220921-C-T
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_182961.4(SYNE1):c.21782G>A(p.Arg7261Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,614,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R7261R) has been classified as Likely benign.
Frequency
Consequence
NM_182961.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SYNE1 | NM_182961.4 | c.21782G>A | p.Arg7261Gln | missense_variant | Exon 119 of 146 | ENST00000367255.10 | NP_892006.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000263 AC: 40AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000955 AC: 24AN: 251332Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135824
GnomAD4 exome AF: 0.0000356 AC: 52AN: 1461824Hom.: 0 Cov.: 32 AF XY: 0.0000344 AC XY: 25AN XY: 727216
GnomAD4 genome AF: 0.000256 AC: 39AN: 152286Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17AN XY: 74462
ClinVar
Submissions by phenotype
not provided Uncertain:4
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 higher than would generally be expected for pathogenic variants in this gene. (http://gnomad.broadinstitute.org) Polyphen and MutationTaster predict this amino acid change may be benign. -
In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
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not specified Uncertain:1
Variant summary: SYNE1 c.21569G>A (p.Arg7190Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 251332 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SYNE1 causing SYNE1-Related Disorders, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.21569G>A in individuals affected with SYNE1-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 432582). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Inborn genetic diseases Uncertain:1
The c.21569G>A (p.R7190Q) alteration is located in exon 118 (coding exon 117) of the SYNE1 gene. This alteration results from a G to A substitution at nucleotide position 21569, causing the arginine (R) at amino acid position 7190 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant Uncertain:1
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 7190 of the SYNE1 protein (p.Arg7190Gln). This variant is present in population databases (rs61742716, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 432582). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Emery-Dreifuss muscular dystrophy 4, autosomal dominant Uncertain:1
This sequence variant is a single nucleotide substitution (G>A) at position 21569 of the coding sequence of the SYNE1 gene that results in an arginine to glutamine amino acid change at residue 7190 of the SYNE1 protein. This variant falls in spectrin repeat 62 of the SYNE1 protein. This is a previously reported variant (ClinVar 432582) that has not been observed in the literature in individuals with SYNE1-related disease, to our knowledge. This variant is present in 31 of 282738 alleles (0.0110%) in the gnomAD population dataset. Multiple bioinformatic tools predict that this arginine to glutamine amino acid change would be neutral, and the Arg7190 residue at this position is poorly conserved across the vertebrate species examined. Studies examining the functiol consequence of this variant have not been performed, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: BP1, BP4, PM2 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at