21-46125782-C-A
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_001849.4(COL6A2):c.1970-3C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,611,200 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001849.4 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL6A2 | NM_001849.4 | c.1970-3C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000300527.9 | |||
COL6A2 | NM_058174.3 | c.1970-3C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000397763.6 | |||
COL6A2 | NM_058175.3 | c.1970-3C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL6A2 | ENST00000300527.9 | c.1970-3C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_001849.4 | P1 | |||
COL6A2 | ENST00000397763.6 | c.1970-3C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 5 | NM_058174.3 | ||||
COL6A2 | ENST00000409416.6 | c.1970-3C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 5 | |||||
COL6A2 | ENST00000413758.1 | c.641-3C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00114 AC: 174AN: 152206Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00101 AC: 250AN: 248088Hom.: 0 AF XY: 0.000867 AC XY: 117AN XY: 134960
GnomAD4 exome AF: 0.00186 AC: 2708AN: 1458876Hom.: 3 Cov.: 36 AF XY: 0.00177 AC XY: 1286AN XY: 725410
GnomAD4 genome ? AF: 0.00114 AC: 174AN: 152324Hom.: 0 Cov.: 33 AF XY: 0.000926 AC XY: 69AN XY: 74478
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 25, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 19, 2022 | Identified in two patients with Bethlem myopathy (Lampe et al., 2005; Tagliavini et al., 2014); however, functional characterization of the variant was not performed; Identified in five patients with limb-girdle muscular dystrophy type 1A who were heterozygous for this variant and did not have a second COL6A2 variant (Nallamilli et al., 2018); however, information regarding parental testing was not provided; Reported previously as a variant of uncertain significance in a patient with progressive muscle weakness in all extremities, who also had a pathogenic variant in the VCP gene and received a diagnosis of VCP myopathy (Bazrafshan et al., 2021); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 15689448, 24907562, 27656840, 30564623, 33567613) - |
Tip-toe gait Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino | Feb 14, 2022 | - - |
Myosclerosis Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Bethlem myopathy 1A Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | - - |
Collagen 6-related myopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Ullrich congenital muscular dystrophy 1A;CN029274:Bethlem myopathy 1A Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at