chr21-46128433-G-A

Variant names:

• chr21-46128433-G-A
• rs7280485
• NM_001849.4:c.2461+1892G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001849.4(COL6A2):​c.2461+1892G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 152,124 control chromosomes in the GnomAD database, including 9,287 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.33 (9287 hom., cov: 34)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00400
• Publications: 7 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.2461+1892G>A		intron_variant	Intron 27 of 27	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.2462-763G>A		intron_variant	Intron 27 of 27		NP_478054.2
COL6A2	NM_058175.3	c.2462-470G>A		intron_variant	Intron 27 of 27		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.2461+1892G>A		intron_variant	Intron 27 of 27	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.2462-763G>A		intron_variant	Intron 27 of 27	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.2462-470G>A		intron_variant	Intron 26 of 26	5		ENSP00000387115.1

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49520 AN: 152006 Hom.: 9272 Cov.: 34

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.452

Gnomad AMR AF: 0.482

Gnomad ASJ AF: 0.335

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.445

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.339

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

GnomAD4 genome AF: 0.326 AC: 49542 AN: 152124 Hom.: 9287 Cov.: 34 AF XY: 0.331 AC XY: 24631 AN XY: 74352

African (AFR) AF: 0.139 AC: 5752 AN: 41528

American (AMR) AF: 0.483 AC: 7374 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 1162 AN: 3468

East Asian (EAS) AF: 0.449 AC: 2317 AN: 5166

South Asian (SAS) AF: 0.270 AC: 1302 AN: 4824

European-Finnish (FIN) AF: 0.445 AC: 4703 AN: 10578

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.379 AC: 25741 AN: 67970

Other (OTH) AF: 0.336 AC: 710 AN: 2112

Alfa AF: 0.357 Hom.: 17612

Bravo AF: 0.322

Asia WGS AF: 0.362 AC: 1258 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.3
DANN	Benign	0.48
PhyloP100		-0.0040
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs7280485; hg19: chr21-47548347;