chr21-46125462-C-A

Position:

• chr21-46125462-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001849.4(COL6A2):​c.1817-3C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: COL6A2 NM_001849.4 splice_region, intron
• Scores: Splicing: ADA: 0.9989
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.90

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1817-3C>A		splice_region_variant, intron_variant		ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1817-3C>A		splice_region_variant, intron_variant			NP_478054.2
COL6A2	NM_058175.3	c.1817-3C>A		splice_region_variant, intron_variant			NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1817-3C>A		splice_region_variant, intron_variant		1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000413758.1	c.485C>A	p.Pro162Gln	missense_variant	10/11	3		ENSP00000395751.1
COL6A2	ENST00000397763.6	c.1817-3C>A		splice_region_variant, intron_variant		5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.1817-3C>A		splice_region_variant, intron_variant		5		ENSP00000387115.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250502 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135750

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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460576 Hom.: 0 Cov.: 51 AF XY: 0.00000275 AC XY: 2 AN XY: 726566

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bethlem myopathy 1A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 02, 2024

This sequence change falls in intron 24 of the COL6A2 gene. It does not directly change the encoded amino acid sequence of the COL6A2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with COL6A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1023434). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.0085	T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.40	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.18
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.18	T
MutPred		0.39		Loss of catalytic residue at P161 (P = 0.0116);
MVP		0.89
ClinPred		0.17	T
GERP RS		4.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.40		Position offset: -45
DS_AL_spliceai		0.23		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs112645828; hg19: chr21-47545376;