rs35879189

Variant names:

• chr2-237336220-TGCA-T
• rs35879189
• NM_004369.4:c.8877_8879delTGC

Your query was ambiguous. Multiple possible variants found:

• chr2-237336220-TGCA-T
• chr2-237336220-TGCA-TGCAGCA
• chr2-237336220-TGCA-TGCAGCAGCA

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BA1

The NM_004369.4(COL6A3):​c.8877_8879delTGC​(p.Ala2960del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,613,878 control chromosomes in the GnomAD database, including 10,585 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (626 hom., cov: 31)
  • Exomes 𝑓: 0.11 (9959 hom.)
• Consequence: COL6A3 NM_004369.4 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.80
• Publications: 7 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 -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_004369.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 2-237336220-TGCA-T is Benign according to our data. Variant chr2-237336220-TGCA-T is described in ClinVar as Benign. ClinVar VariationId is 95012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.116 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.8877_8879delTGC	p.Ala2960del	disruptive_inframe_deletion	Exon 40 of 44	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.8259_8261delTGC	p.Ala2754del	disruptive_inframe_deletion	Exon 39 of 43	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.7056_7058delTGC	p.Ala2353del	disruptive_inframe_deletion	Exon 37 of 41	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.8877_8879delTGC	p.Ala2960del	disruptive_inframe_deletion	Exon 40 of 44	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.7056_7058delTGC	p.Ala2353del	disruptive_inframe_deletion	Exon 37 of 41	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000353578.9	TSL:5	c.8259_8261delTGC	p.Ala2754del	disruptive_inframe_deletion	Exon 39 of 43	ENSP00000315873.4	P12111-2

Frequencies

GnomAD3 genomes AF: 0.0784 AC: 11923 AN: 152138 Hom.: 626 Cov.: 31

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.0593

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.00942

Gnomad SAS AF: 0.0766

Gnomad FIN AF: 0.0935

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.0784

GnomAD2 exomes AF: 0.0856 AC: 21412 AN: 250082 AF XY: 0.0887

Gnomad AFR exome AF: 0.0196

Gnomad AMR exome AF: 0.0459

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.0101

Gnomad FIN exome AF: 0.0984

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.0857

GnomAD4 exome AF: 0.111 AC: 162654 AN: 1461622 Hom.: 9959 AF XY: 0.110 AC XY: 80303 AN XY: 727108

African (AFR) AF: 0.0182 AC: 610 AN: 33480

American (AMR) AF: 0.0490 AC: 2190 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 3104 AN: 26136

East Asian (EAS) AF: 0.00967 AC: 384 AN: 39698

South Asian (SAS) AF: 0.0774 AC: 6672 AN: 86252

European-Finnish (FIN) AF: 0.0981 AC: 5222 AN: 53250

Middle Eastern (MID) AF: 0.0536 AC: 309 AN: 5760

European-Non Finnish (NFE) AF: 0.124 AC: 137981 AN: 1111936

Other (OTH) AF: 0.102 AC: 6182 AN: 60386

GnomAD4 genome AF: 0.0783 AC: 11919 AN: 152256 Hom.: 626 Cov.: 31 AF XY: 0.0759 AC XY: 5650 AN XY: 74436

African (AFR) AF: 0.0213 AC: 885 AN: 41570

American (AMR) AF: 0.0593 AC: 906 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 392 AN: 3466

East Asian (EAS) AF: 0.00944 AC: 49 AN: 5190

South Asian (SAS) AF: 0.0769 AC: 371 AN: 4826

European-Finnish (FIN) AF: 0.0935 AC: 991 AN: 10594

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 8016 AN: 68002

Other (OTH) AF: 0.0771 AC: 163 AN: 2114

Alfa AF: 0.0613 Hom.: 87

Bravo AF: 0.0747

Asia WGS AF: 0.0470 AC: 165 AN: 3478

EpiCase AF: 0.116

EpiControl AF: 0.115

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Collagen 6-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
Mutation Taster		=83/17	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs35879189; hg19: chr2-238244863; COSMIC: COSV55082643; COSMIC: COSV55082643;