rs117345850

Variant names:

• chr2-237368554-G-A
• rs117345850
• NM_004369.4:c.4900+9C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-237368554-G-A
• chr2-237368554-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004369.4(COL6A3):​c.4900+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000524 in 1,613,802 control chromosomes in the GnomAD database, including 8 homozygotes. 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 0.00038 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (6 hom.)
• Consequence: COL6A3 NM_004369.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -0.393
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-237368554-G-A is Benign according to our data. Variant chr2-237368554-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 285987.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000381 (58/152198) while in subpopulation EAS AF = 0.00599 (31/5174). AF 95% confidence interval is 0.00434. There are 2 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.4900+9C>T		intron	N/A	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.4282+9C>T		intron	N/A	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.3079+9C>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.4900+9C>T		intron	N/A	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.3079+9C>T		intron	N/A	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000353578.9	TSL:5	c.4282+9C>T		intron	N/A	ENSP00000315873.4	P12111-2

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152080 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00598

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000654 AC: 164 AN: 250956 AF XY: 0.000634

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.00370

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000538 AC: 787 AN: 1461604 Hom.: 6 Cov.: 33 AF XY: 0.000539 AC XY: 392 AN XY: 727032

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

American (AMR) AF: 0.000313 AC: 14 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00402 AC: 105 AN: 26136

East Asian (EAS) AF: 0.0124 AC: 492 AN: 39688

South Asian (SAS) AF: 0.000696 AC: 60 AN: 86244

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53414

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000711 AC: 79 AN: 1111774

Other (OTH) AF: 0.000530 AC: 32 AN: 60384

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152198 Hom.: 2 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74418

African (AFR) AF: 0.0000482 AC: 2 AN: 41514

American (AMR) AF: 0.000196 AC: 3 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00599 AC: 31 AN: 5174

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4806

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68002

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000269 Hom.: 0

Bravo AF: 0.000385

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	COL6A3-related disorder (1)
-	-	1	Collagen 6-related myopathy (1)
-	1	-	Dystonia 27 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.41
DANN	Benign	0.45
PhyloP100		-0.39
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: rs117345850; hg19: chr2-238277197;