rs1555873353

Variant names:

• chr21-46117386-CCCTTCTCCTTCAGGGCAAGCTGGGGCGCATCGGACCTCCTGGCT-C
• rs1555873353
• NM_001849.4:c.1000-13_1030delCCTTCTCCTTCAGGGCAAGCTGGGGCGCATCGGACCTCCTGGCT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001849.4(COL6A2):​c.1000-13_1030delCCTTCTCCTTCAGGGCAAGCTGGGGCGCATCGGACCTCCTGGCT​(p.Gly334fs) variant causes a frameshift, splice acceptor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 34)
• Consequence: COL6A2 NM_001849.4 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.44
• Publications: 0 publications found

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]

COL6A2 Gene-Disease associations (from GenCC):

• collagen 6-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1B

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: G2P
• Bethlem myopathy 1A

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Bethlem myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ullrich congenital muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myosclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 21-46117386-CCCTTCTCCTTCAGGGCAAGCTGGGGCGCATCGGACCTCCTGGCT-C is Pathogenic according to our data. Variant chr21-46117386-CCCTTCTCCTTCAGGGCAAGCTGGGGCGCATCGGACCTCCTGGCT-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 476445.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1000-13_1030delCCTTCTCCTTCAGGGCAAGCTGGGGCGCATCGGACCTCCTGGCT	p.Gly334fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 11 of 28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1000-13_1030delCCTTCTCCTTCAGGGCAAGCTGGGGCGCATCGGACCTCCTGGCT	p.Gly334fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 11 of 28		NP_478054.2
COL6A2	NM_058175.3	c.1000-13_1030delCCTTCTCCTTCAGGGCAAGCTGGGGCGCATCGGACCTCCTGGCT	p.Gly334fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 11 of 28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1000-13_1030delCCTTCTCCTTCAGGGCAAGCTGGGGCGCATCGGACCTCCTGGCT	p.Gly334fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 11 of 28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.1000-13_1030delCCTTCTCCTTCAGGGCAAGCTGGGGCGCATCGGACCTCCTGGCT	p.Gly334fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 11 of 28	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.1000-13_1030delCCTTCTCCTTCAGGGCAAGCTGGGGCGCATCGGACCTCCTGGCT	p.Gly334fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 10 of 27	5		ENSP00000387115.1
COL6A2	ENST00000485591.1	n.656-13_686delCCTTCTCCTTCAGGGCAAGCTGGGGCGCATCGGACCTCCTGGCT		splice_acceptor_variant, splice_region_variant, intron_variant, non_coding_transcript_exon_variant	Exon 7 of 7	3

Frequencies

GnomAD3 genomes Cov.: 34

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bethlem myopathy 1A Pathogenic:1

May 10, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, donor and acceptor splice site variants are typically loss-of-function (PMID: 16199547), and loss-of-function variants in COL6A2 are known to be pathogenic in autosomal recessive COL6A2-related conditions (PMID: 21280092, 20976770). In addition, other mutations that delete a portion of the protein, such as those resulting in exon skipping, have also been identified in autosomal dominant COL6A2-related conditions (PMID: 1788629). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic. While this particular variant has not been reported in the literature, a similar variant also affecting the donor splice site in intron 10 (c.1000-2A>G) has been reported in the heterozygous state in an individual affected with Bethlem myopathy (PMID: 17886299). In this individual the splice site variant was shown to cause skipping of exon 11, resulting in autosomal dominant disease. This sequence change affects an acceptor splice site in intron 10 of the COL6A2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant also deletes the first 30 nucleotides of exon 11, disrupting 10 amino acid residues. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555873353; hg19: chr21-47537300;