rs7579816

Variant names:

• chr2-237381516-T-C
• rs7579816
• NM_004369.4:c.1313-17A>G

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.1313-17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00489 in 1,579,334 control chromosomes in the GnomAD database, including 298 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (155 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (143 hom.)
• Consequence: COL6A3 NM_004369.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.06
• Publications: 2 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: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
• collagen 6-related myopathy

  Inheritance: AR, SD, AD 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics, Illumina
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AR, AD, SD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-0.88).
• BP6: Variant 2-237381516-T-C is Benign according to our data. Variant chr2-237381516-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0813 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.1313-17A>G		intron	N/A	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.695-17A>G		intron	N/A	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.92-17A>G		intron	N/A	NP_476507.3	P12111-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.1313-17A>G		intron	N/A	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.92-17A>G		intron	N/A	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000392004.7	TSL:1	c.695-17A>G		intron	N/A	ENSP00000375861.3	P12111-5

Frequencies

GnomAD3 genomes AF: 0.0241 AC: 3664 AN: 152156 Hom.: 155 Cov.: 33

Gnomad AFR AF: 0.0835

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00923

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00645 AC: 1476 AN: 228966 AF XY: 0.00436

Gnomad AFR exome AF: 0.0841

Gnomad AMR exome AF: 0.00440

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000635

Gnomad OTH exome AF: 0.00374

GnomAD4 exome AF: 0.00284 AC: 4047 AN: 1427060 Hom.: 143 Cov.: 28 AF XY: 0.00250 AC XY: 1775 AN XY: 711248

African (AFR) AF: 0.0872 AC: 2886 AN: 33100

American (AMR) AF: 0.00476 AC: 211 AN: 44354

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25946

East Asian (EAS) AF: 0.00 AC: 0 AN: 39576

South Asian (SAS) AF: 0.000644 AC: 55 AN: 85428

European-Finnish (FIN) AF: 0.0000254 AC: 1 AN: 39436

Middle Eastern (MID) AF: 0.0131 AC: 75 AN: 5720

European-Non Finnish (NFE) AF: 0.000385 AC: 421 AN: 1093882

Other (OTH) AF: 0.00666 AC: 397 AN: 59618

GnomAD4 genome AF: 0.0242 AC: 3680 AN: 152274 Hom.: 155 Cov.: 33 AF XY: 0.0234 AC XY: 1740 AN XY: 74452

African (AFR) AF: 0.0836 AC: 3473 AN: 41524

American (AMR) AF: 0.00921 AC: 141 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68028

Other (OTH) AF: 0.0128 AC: 27 AN: 2112

Alfa AF: 0.0145 Hom.: 33

Bravo AF: 0.0266

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.18
DANN	Benign	0.69
PhyloP100		-2.1
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: rs7579816; hg19: chr2-238290159;