rs59232721

Variant names:

• chr2-237342196-G-A
• rs59232721
• NM_004369.4:c.7669-35C>T

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.7669-35C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.084 in 1,531,106 control chromosomes in the GnomAD database, including 5,950 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.066 (395 hom., cov: 32)
  • Exomes 𝑓: 0.086 (5555 hom.)
• Consequence: COL6A3 NM_004369.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.827
• Publications: 1 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-237342196-G-A is Benign according to our data. Variant chr2-237342196-G-A is described in ClinVar as Benign. ClinVar VariationId is 94993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0874 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.7669-35C>T		intron	N/A	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.7051-35C>T		intron	N/A	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.5848-35C>T		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.7669-35C>T		intron	N/A	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.5848-35C>T		intron	N/A	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000353578.9	TSL:5	c.7051-35C>T		intron	N/A	ENSP00000315873.4	P12111-2

Frequencies

GnomAD3 genomes AF: 0.0655 AC: 9965 AN: 152108 Hom.: 392 Cov.: 32

Gnomad AFR AF: 0.0413

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0481

Gnomad ASJ AF: 0.0933

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0699

Gnomad FIN AF: 0.0581

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0892

Gnomad OTH AF: 0.0565

GnomAD2 exomes AF: 0.0672 AC: 16305 AN: 242500 AF XY: 0.0702

Gnomad AFR exome AF: 0.0397

Gnomad AMR exome AF: 0.0331

Gnomad ASJ exome AF: 0.0980

Gnomad EAS exome AF: 0.000278

Gnomad FIN exome AF: 0.0599

Gnomad NFE exome AF: 0.0894

Gnomad OTH exome AF: 0.0747

GnomAD4 exome AF: 0.0860 AC: 118624 AN: 1378880 Hom.: 5555 Cov.: 22 AF XY: 0.0861 AC XY: 59382 AN XY: 689902

African (AFR) AF: 0.0381 AC: 1211 AN: 31804

American (AMR) AF: 0.0350 AC: 1539 AN: 44034

Ashkenazi Jewish (ASJ) AF: 0.0918 AC: 2341 AN: 25506

East Asian (EAS) AF: 0.000280 AC: 11 AN: 39268

South Asian (SAS) AF: 0.0753 AC: 6284 AN: 83492

European-Finnish (FIN) AF: 0.0622 AC: 3309 AN: 53164

Middle Eastern (MID) AF: 0.0909 AC: 510 AN: 5612

European-Non Finnish (NFE) AF: 0.0945 AC: 98145 AN: 1038346

Other (OTH) AF: 0.0915 AC: 5274 AN: 57654

GnomAD4 genome AF: 0.0656 AC: 9983 AN: 152226 Hom.: 395 Cov.: 32 AF XY: 0.0616 AC XY: 4587 AN XY: 74420

African (AFR) AF: 0.0416 AC: 1727 AN: 41516

American (AMR) AF: 0.0480 AC: 734 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0933 AC: 324 AN: 3472

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5194

South Asian (SAS) AF: 0.0707 AC: 341 AN: 4820

European-Finnish (FIN) AF: 0.0581 AC: 615 AN: 10582

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0893 AC: 6072 AN: 68020

Other (OTH) AF: 0.0549 AC: 116 AN: 2112

Alfa AF: 0.0774 Hom.: 166

Bravo AF: 0.0651

Asia WGS AF: 0.0310 AC: 108 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.7
DANN	Benign	0.49
PhyloP100		-0.83
BranchPoint Hunter		1.0
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: rs59232721; hg19: chr2-238250839;