rs2646263

Variant names:

• chr2-237348710-A-G
• rs2646263
• NM_004369.4:c.6880-47T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004369.4(COL6A3):​c.6880-47T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 1,555,482 control chromosomes in the GnomAD database, including 15,671 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2658 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13013 hom.)
• Consequence: COL6A3 NM_004369.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.72
• Publications: 4 publications found

Genes affected

COL6A3 (HGNC:2213): (collagen type VI alpha 3 chain) This gene encodes the alpha-3 chain, one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The alpha-3 chain of type VI collagen is much larger than the alpha-1 and -2 chains. This difference in size is largely due to an increase in the number of subdomains, similar to von Willebrand Factor type A domains, that are found in the amino terminal globular domain of all the alpha chains. 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 the type VI collagen genes are associated with Bethlem myopathy, a rare autosomal dominant proximal myopathy with early childhood onset. Mutations in this gene are also a cause of Ullrich congenital muscular dystrophy, also referred to as Ullrich scleroatonic muscular dystrophy, an autosomal recessive congenital myopathy that is more severe than Bethlem myopathy. Multiple transcript variants have been identified, but the full-length nature of only some of these variants has been described. [provided by RefSeq, Jun 2009]

COL6A3 Gene-Disease associations (from GenCC):

• Bethlem myopathy 1A

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
• collagen 6-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1C

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• dystonia 27

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Illumina, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AR, AD, SD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• Bethlem myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ullrich congenital muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-237348710-A-G is Benign according to our data. Variant chr2-237348710-A-G is described in ClinVar as Benign. ClinVar VariationId is 94972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004369.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	NM_004369.4	MANE Select	c.6880-47T>C		intron	N/A	NP_004360.2
	COL6A3	NM_057167.4		c.6262-47T>C		intron	N/A	NP_476508.2
	COL6A3	NM_057166.5		c.5059-47T>C		intron	N/A	NP_476507.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.6880-47T>C		intron	N/A	ENSP00000295550.4
	COL6A3	ENST00000472056.5	TSL:1	c.5059-47T>C		intron	N/A	ENSP00000418285.1
	COL6A3	ENST00000353578.9	TSL:5	c.6262-47T>C		intron	N/A	ENSP00000315873.4

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26193 AN: 152024 Hom.: 2660 Cov.: 32

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.0890

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.0529

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.181

GnomAD2 exomes AF: 0.147 AC: 36276 AN: 246214 AF XY: 0.144

Gnomad AFR exome AF: 0.284

Gnomad AMR exome AF: 0.198

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.0512

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.131 AC: 184359 AN: 1403340 Hom.: 13013 Cov.: 23 AF XY: 0.131 AC XY: 92037 AN XY: 701248

African (AFR) AF: 0.285 AC: 9238 AN: 32432

American (AMR) AF: 0.198 AC: 8792 AN: 44390

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 4316 AN: 25750

East Asian (EAS) AF: 0.0541 AC: 2127 AN: 39348

South Asian (SAS) AF: 0.146 AC: 12324 AN: 84458

European-Finnish (FIN) AF: 0.122 AC: 6502 AN: 53136

Middle Eastern (MID) AF: 0.209 AC: 1180 AN: 5658

European-Non Finnish (NFE) AF: 0.124 AC: 131733 AN: 1059654

Other (OTH) AF: 0.139 AC: 8147 AN: 58514

GnomAD4 genome AF: 0.172 AC: 26210 AN: 152142 Hom.: 2658 Cov.: 32 AF XY: 0.172 AC XY: 12812 AN XY: 74360

African (AFR) AF: 0.272 AC: 11274 AN: 41484

American (AMR) AF: 0.200 AC: 3062 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 607 AN: 3466

East Asian (EAS) AF: 0.0526 AC: 272 AN: 5168

South Asian (SAS) AF: 0.140 AC: 671 AN: 4802

European-Finnish (FIN) AF: 0.121 AC: 1287 AN: 10612

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8509 AN: 68006

Other (OTH) AF: 0.179 AC: 379 AN: 2116

Alfa AF: 0.158 Hom.: 910

Bravo AF: 0.182

Asia WGS AF: 0.104 AC: 363 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0020
DANN	Benign	0.12
PhyloP100		-3.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs2646263; hg19: chr2-238257353; COSMIC: COSV107337571;