rs1057518925

Variant names:

• chr21-46114006-A-G
• rs1057518925
• NM_001849.4:c.736-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001849.4(COL6A2):​c.736-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: COL6A2 NM_001849.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.18
• Publications: 1 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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.021568628 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.7, offset of 9, new splice context is: cctcgtttcggtgctacaAGgtg. 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
• PP5: Variant 21-46114006-A-G is Pathogenic according to our data. Variant chr21-46114006-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 374143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.736-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 27	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.736-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 27		NP_478054.2
COL6A2	NM_058175.3	c.736-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 27		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.736-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 27	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000485591.1	n.390A>G		non_coding_transcript_exon_variant	Exon 1 of 7	3
COL6A2	ENST00000397763.6	c.736-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 27	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.736-2A>G		splice_acceptor_variant, intron_variant	Intron 3 of 26	5		ENSP00000387115.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fatigue;C0026850:Muscular dystrophy;C1856877:Hyperextensible hand joints;C1858127:Limb-girdle muscle weakness Pathogenic:1

Nov 17, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bethlem myopathy 1A Pathogenic:1

Jun 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 4 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-related 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with autosomal dominant COL6A2-related conditions (PMID: 24801232, 25535305, 33537799). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 374143). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 33537799). For these reasons, this variant has been classified as Pathogenic. -

Ullrich congenital muscular dystrophy 1A Pathogenic:1

Oct 02, 2021

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported as pathogenic (ClinVar ID: VCV000523809.3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:1

Jun 12, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		8.2
GERP RS		4.1
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.44		Position offset: 11
DS_AL_spliceai		0.98		Position offset: 2
DS_DG_spliceai		0.20		Position offset: 10

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

Other links and lift over

dbSNP: rs1057518925; hg19: chr21-47533920;