rs115387170

Variant names:

• chr2-237378670-A-G
• rs115387170
• NM_004369.4:c.2463T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004369.4(COL6A3):​c.2463T>C​(p.Ser821Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 1,613,240 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (10 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.106
• Publications: 0 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 2-237378670-A-G is Benign according to our data. Variant chr2-237378670-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.106 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0027 (412/152352) while in subpopulation NFE AF = 0.00394 (268/68028). AF 95% confidence interval is 0.00355. There are 2 homozygotes in GnomAd4. There are 204 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR,SD gene

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.2463T>C	p.Ser821Ser	synonymous	Exon 6 of 44	NP_004360.2
	COL6A3	NM_057167.4		c.1845T>C	p.Ser615Ser	synonymous	Exon 5 of 43	NP_476508.2
	COL6A3	NM_057165.5		c.1845T>C	p.Ser615Ser	synonymous	Exon 5 of 8	NP_476506.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.2463T>C	p.Ser821Ser	synonymous	Exon 6 of 44	ENSP00000295550.4
	COL6A3	ENST00000392004.7	TSL:1	c.1845T>C	p.Ser615Ser	synonymous	Exon 5 of 8	ENSP00000375861.3
	COL6A3	ENST00000472056.5	TSL:1	c.677-1326T>C		intron	N/A	ENSP00000418285.1

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 412 AN: 152234 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00357

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00394

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00238 AC: 598 AN: 251440 AF XY: 0.00255

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00291

Gnomad NFE exome AF: 0.00364

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00327 AC: 4775 AN: 1460888 Hom.: 10 Cov.: 33 AF XY: 0.00324 AC XY: 2352 AN XY: 726748

African (AFR) AF: 0.00102 AC: 34 AN: 33446

American (AMR) AF: 0.00203 AC: 91 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000727 AC: 19 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000568 AC: 49 AN: 86196

European-Finnish (FIN) AF: 0.00320 AC: 171 AN: 53416

Middle Eastern (MID) AF: 0.0103 AC: 51 AN: 4960

European-Non Finnish (NFE) AF: 0.00373 AC: 4144 AN: 1112010

Other (OTH) AF: 0.00358 AC: 216 AN: 60300

GnomAD4 genome AF: 0.00270 AC: 412 AN: 152352 Hom.: 2 Cov.: 33 AF XY: 0.00274 AC XY: 204 AN XY: 74516

African (AFR) AF: 0.000673 AC: 28 AN: 41586

American (AMR) AF: 0.00359 AC: 55 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00357 AC: 38 AN: 10630

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00394 AC: 268 AN: 68028

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00341 Hom.: 0

Bravo AF: 0.00277

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00556

EpiControl AF: 0.00640

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	Ullrich congenital muscular dystrophy 1A;C4225336:Dystonia 27;CN029274:Bethlem myopathy 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.9
DANN	Benign	0.70
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism

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: rs115387170; hg19: chr2-238287313; COSMIC: COSV55090080;