rs1555873084

Positions:

• chr21-46116768-A-C
• chr21-46116768-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001849.4(COL6A2):​c.955-2A>C variant causes a splice acceptor, intron 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: 32)
• Consequence: COL6A2 NM_001849.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.19

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.014379085 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8, offset of -48, new splice context is: ccctccttcctgctgctcAGggc. 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 21-46116768-A-C is Pathogenic according to our data. Variant chr21-46116768-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 1691316.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.955-2A>C		splice_acceptor_variant, intron_variant		ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.955-2A>C		splice_acceptor_variant, intron_variant			NP_478054.2
COL6A2	NM_058175.3	c.955-2A>C		splice_acceptor_variant, intron_variant			NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.955-2A>C		splice_acceptor_variant, intron_variant		1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.955-2A>C		splice_acceptor_variant, intron_variant		5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.955-2A>C		splice_acceptor_variant, intron_variant		5		ENSP00000387115.1
COL6A2	ENST00000485591.1	n.611-2A>C		splice_acceptor_variant, intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ullrich congenital muscular dystrophy 1A;CN029274:Bethlem myopathy 1A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology

May 18, 2022

The c.955-2A>C variant is not present in publicly available population databases like 1000 Genomes, Exome Variant Server (EVS), Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD) and Indian Exome Database. The variant is not present in our in-house exome database. The variant was previously identified in similarly affected patients, published in literatures (PMID: 34167565, 29419890, 27453230, 20976770, 18366090, 15689448) and reported to Human Genome Mutation Database (HGMD ID: CS050380). In-silico pathogenicity prediction programs like MutationTaster2, CADD, Varsome, HSF3.1 etc. predicted this variant to be likely deleterious. Different algorithms to predict mRNA splicing abnormalities, predicted this variant to potentially affect splicing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	32
DANN	Uncertain	0.98
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.97	D
GERP RS		4.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.80
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.56		Position offset: 26
DS_AL_spliceai		0.98		Position offset: 2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-47536682;