rs1555873356
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_001849.4(COL6A2):c.1000-2A>C variant causes a splice acceptor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 34)
Consequence
COL6A2
NM_001849.4 splice_acceptor
NM_001849.4 splice_acceptor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.50
Genes affected
COL6A2 (HGNC:2212): (collagen type VI alpha 2 chain) This gene encodes one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The product of this gene contains several domains similar to von Willebrand Factor type A domains. These domains have been shown to bind extracellular matrix proteins, an interaction that explains the importance of this collagen in organizing matrix components. Mutations in this gene are associated with Bethlem myopathy and Ullrich scleroatonic muscular dystrophy. Three transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.017320262 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.9, offset of 6, new splice context is: cccttctccttccgggcaAGctg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 21-46117398-A-C is Pathogenic according to our data. Variant chr21-46117398-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 476446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL6A2 | NM_001849.4 | c.1000-2A>C | splice_acceptor_variant | ENST00000300527.9 | |||
COL6A2 | NM_058174.3 | c.1000-2A>C | splice_acceptor_variant | ENST00000397763.6 | |||
COL6A2 | NM_058175.3 | c.1000-2A>C | splice_acceptor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL6A2 | ENST00000300527.9 | c.1000-2A>C | splice_acceptor_variant | 1 | NM_001849.4 | P1 | |||
COL6A2 | ENST00000397763.6 | c.1000-2A>C | splice_acceptor_variant | 5 | NM_058174.3 | ||||
COL6A2 | ENST00000409416.6 | c.1000-2A>C | splice_acceptor_variant | 5 | |||||
COL6A2 | ENST00000485591.1 | n.656-2A>C | splice_acceptor_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD3 genomes
?
Cov.:
34
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 34
GnomAD4 genome
?
Cov.:
34
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 24, 2018 | The c.1000-2 A>C splice site variant in the COL6A2 gene destroys the canonical splice acceptor site for intron 10. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. This splice site variant occurs within the the triple helical (TH) domain of collagen VI, a region that is well-conserved across species. Additionally, this variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.1000-2 A>C as a pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 05, 2017 | - - |
Bethlem myopathy 1A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 15, 2022 | For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 17886299). ClinVar contains an entry for this variant (Variation ID: 476446). Disruption of this splice site has been observed in individual(s) with autosomal dominant COL6A2-related conditions (PMID: 17886299; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 10 of the COL6A2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL6A2 are known to be disease-causing for autosomal recessive COL6A2 conditions (PMID: 21280092, 20976770). However, certain variants affecting donor or acceptor splice sites in the triple helical domain of COL6A2 are expected to result in in-frame exon skipping and have been reported to cause autosomal dominant COL6A2-related conditions (PMID: 18366090). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 8
DS_AL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at