rs749974929

chr21-46121554-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Moderate PP3_Strong PP5_Moderate

The NM_001849.4(COL6A2):c.1459-2A>G variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000411 in 1,460,496 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: COL6A2 NM_001849.4 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.39

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.020261439 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• 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 21-46121554-A-G is Pathogenic according to our data. Variant chr21-46121554-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 476452.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-46121554-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.1459-2A>G		splice_acceptor_variant		ENST00000300527.9
COL6A2	NM_058174.3	c.1459-2A>G		splice_acceptor_variant		ENST00000397763.6
COL6A2	NM_058175.3	c.1459-2A>G		splice_acceptor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.1459-2A>G		splice_acceptor_variant		1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.1459-2A>G		splice_acceptor_variant		5	NM_058174.3
COL6A2	ENST00000409416.6	c.1459-2A>G		splice_acceptor_variant		5
COL6A2	ENST00000413758.1	c.82-2A>G		splice_acceptor_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249770 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135558

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460496 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726550

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Bethlem myopathy 1A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 21, 2017

This sequence change affects an acceptor splice site in intron 17 of the COL6A2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs749974929, ExAC 0.002%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in two siblings affected with Ullrich congenital myopathy (UCMD) (PMID: 11381124). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. Experimental studies have shown that this variant leads to the use of a cryptic splice site in exon 18, causing a frameshift and premature termination codon which is expected to result in nonsense mediated decay (PMID: 11381124). This variant is also reported to occur de novo in an unrelated individual affected with UCMD. A second pathogenic variant was not found in this individual (PMID: 11381124). For these reasons, this variant has been classified as Pathogenic. -

Ullrich congenital muscular dystrophy 1B Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 15, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	35
Dann	Uncertain	0.99
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	1.0	D;D;D;D;D
GERP RS		4.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.88		Position offset: 30
DS_AL_spliceai		1.0		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs749974929; hg19: chr21-47541468;