chr21-46120518-G-A
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_001849.4(COL6A2):c.1336G>A(p.Asp446Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000881 in 1,507,332 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D446H) has been classified as Uncertain significance.
Frequency
Consequence
NM_001849.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL6A2 | NM_001849.4 | c.1336G>A | p.Asp446Asn | missense_variant | 16/28 | ENST00000300527.9 | |
COL6A2 | NM_058174.3 | c.1336G>A | p.Asp446Asn | missense_variant | 16/28 | ENST00000397763.6 | |
COL6A2 | NM_058175.3 | c.1336G>A | p.Asp446Asn | missense_variant | 16/28 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL6A2 | ENST00000300527.9 | c.1336G>A | p.Asp446Asn | missense_variant | 16/28 | 1 | NM_001849.4 | P1 | |
COL6A2 | ENST00000397763.6 | c.1336G>A | p.Asp446Asn | missense_variant | 16/28 | 5 | NM_058174.3 | ||
COL6A2 | ENST00000409416.6 | c.1336G>A | p.Asp446Asn | missense_variant | 15/27 | 5 | |||
COL6A2 | ENST00000413758.1 | upstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.000572 AC: 87AN: 152176Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.000418 AC: 45AN: 107528Hom.: 0 AF XY: 0.000404 AC XY: 23AN XY: 56958
GnomAD4 exome AF: 0.000916 AC: 1241AN: 1355156Hom.: 1 Cov.: 32 AF XY: 0.000884 AC XY: 590AN XY: 667224
GnomAD4 genome AF: 0.000572 AC: 87AN: 152176Hom.: 0 Cov.: 34 AF XY: 0.000457 AC XY: 34AN XY: 74338
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 30, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 19, 2023 | Reported as a variant of uncertain clinical significance in multiple individuals with limb-girdle muscular dystrophy in published literature (Punetha et al., 2016; Nallamilli et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30564623, 27854218, 23040494) - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 25, 2016 | - - |
Uncertain significance, criteria provided, single submitter | research | Center for Genetic Medicine Research, Children's National Medical Center | Dec 01, 2015 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 06, 2015 | - - |
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 10, 2024 | - - |
Collagen 6-related myopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Ullrich congenital muscular dystrophy 1A;CN029274:Bethlem myopathy 1A;CN117976:Collagen 6-related myopathy Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Uncertain significance and reported on 05-08-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at