rs111481402

Variant names:

• chr2-237388108-G-A
• rs111481402
• NM_004369.4:c.786C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-237388108-G-A
• chr2-237388108-G-C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_004369.4(COL6A3):​c.786C>T​(p.Leu262Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000579 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00060 (0 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.537
• 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: 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 2-237388108-G-A is Benign according to our data. Variant chr2-237388108-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 290161.
• BP7: Synonymous conserved (PhyloP=0.537 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000414 (63/152196) while in subpopulation NFE AF = 0.000661 (45/68038). AF 95% confidence interval is 0.000507. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	NM_004369.4	MANE Select	c.786C>T	p.Leu262Leu	synonymous	Exon 4 of 44	NP_004360.2
	COL6A3	NM_057167.4		c.168C>T	p.Leu56Leu	synonymous	Exon 3 of 43	NP_476508.2
	COL6A3	NM_057165.5		c.168C>T	p.Leu56Leu	synonymous	Exon 3 of 8	NP_476506.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.786C>T	p.Leu262Leu	synonymous	Exon 4 of 44	ENSP00000295550.4
	COL6A3	ENST00000392004.7	TSL:1	c.168C>T	p.Leu56Leu	synonymous	Exon 3 of 8	ENSP00000375861.3
	COL6A3	ENST00000433762.1	TSL:1	c.786C>T	p.Leu262Leu	synonymous	Exon 4 of 6	ENSP00000389539.1

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000377 AC: 94 AN: 249326 AF XY: 0.000445

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.000618

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000596 AC: 871 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.000606 AC XY: 441 AN XY: 727232

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000224 AC: 10 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000449 AC: 24 AN: 53398

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000730 AC: 812 AN: 1112010

Other (OTH) AF: 0.000364 AC: 22 AN: 60394

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27 AN XY: 74358

African (AFR) AF: 0.0000483 AC: 2 AN: 41450

American (AMR) AF: 0.000524 AC: 8 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000661 AC: 45 AN: 68038

Other (OTH) AF: 0.00143 AC: 3 AN: 2094

Alfa AF: 0.000449 Hom.: 0

Bravo AF: 0.000453

EpiCase AF: 0.000545

EpiControl AF: 0.000652

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	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
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.8
DANN	Benign	0.71
PhyloP100		0.54
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: rs111481402; hg19: chr2-238296751; COSMIC: COSV55103371; COSMIC: COSV55103371;