rs72986111

Variant names:

• chr2-237348585-G-A
• rs72986111
• NM_004369.4:c.6930+28C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-237348585-G-A
• chr2-237348585-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000295550.9(COL6A3):​c.6930+28C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0341 in 1,609,298 control chromosomes in the GnomAD database, including 1,115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (85 hom., cov: 33)
  • Exomes 𝑓: 0.035 (1030 hom.)
• Consequence: COL6A3 ENST00000295550.9 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.86
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-237348585-G-A is Benign according to our data. Variant chr2-237348585-G-A is described in ClinVar as Benign. ClinVar VariationId is 94973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0265 (4039/152246) while in subpopulation SAS AF = 0.0392 (189/4820). AF 95% confidence interval is 0.0348. There are 85 homozygotes in GnomAd4. There are 2054 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 85 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000295550.9. 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.6930+28C>T		intron	N/A	NP_004360.2
	COL6A3	NM_057167.4		c.6312+28C>T		intron	N/A	NP_476508.2
	COL6A3	NM_057166.5		c.5109+28C>T		intron	N/A	NP_476507.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.6930+28C>T		intron	N/A	ENSP00000295550.4
	COL6A3	ENST00000472056.5	TSL:1	c.5109+28C>T		intron	N/A	ENSP00000418285.1
	COL6A3	ENST00000353578.9	TSL:5	c.6312+28C>T		intron	N/A	ENSP00000315873.4

Frequencies

GnomAD3 genomes AF: 0.0266 AC: 4041 AN: 152128 Hom.: 85 Cov.: 33

Gnomad AFR AF: 0.00637

Gnomad AMI AF: 0.0551

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.0392

Gnomad FIN AF: 0.0623

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0360

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.0308 AC: 7676 AN: 249268 AF XY: 0.0326

Gnomad AFR exome AF: 0.00595

Gnomad AMR exome AF: 0.0121

Gnomad ASJ exome AF: 0.0265

Gnomad EAS exome AF: 0.0115

Gnomad FIN exome AF: 0.0563

Gnomad NFE exome AF: 0.0364

Gnomad OTH exome AF: 0.0271

GnomAD4 exome AF: 0.0349 AC: 50898 AN: 1457052 Hom.: 1030 Cov.: 31 AF XY: 0.0351 AC XY: 25478 AN XY: 724930

African (AFR) AF: 0.00446 AC: 149 AN: 33402

American (AMR) AF: 0.0129 AC: 578 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 715 AN: 26094

East Asian (EAS) AF: 0.0103 AC: 409 AN: 39656

South Asian (SAS) AF: 0.0395 AC: 3392 AN: 85802

European-Finnish (FIN) AF: 0.0569 AC: 3034 AN: 53346

Middle Eastern (MID) AF: 0.0122 AC: 70 AN: 5758

European-Non Finnish (NFE) AF: 0.0366 AC: 40581 AN: 1108136

Other (OTH) AF: 0.0327 AC: 1970 AN: 60214

GnomAD4 genome AF: 0.0265 AC: 4039 AN: 152246 Hom.: 85 Cov.: 33 AF XY: 0.0276 AC XY: 2054 AN XY: 74422

African (AFR) AF: 0.00635 AC: 264 AN: 41562

American (AMR) AF: 0.0154 AC: 236 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 94 AN: 3470

East Asian (EAS) AF: 0.0100 AC: 52 AN: 5182

South Asian (SAS) AF: 0.0392 AC: 189 AN: 4820

European-Finnish (FIN) AF: 0.0623 AC: 660 AN: 10590

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0360 AC: 2446 AN: 68012

Other (OTH) AF: 0.0213 AC: 45 AN: 2112

Alfa AF: 0.0329 Hom.: 60

Bravo AF: 0.0228

Asia WGS AF: 0.0370 AC: 130 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.87
CADD	Benign	0.17
DANN	Benign	0.69
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs72986111; hg19: chr2-238257228; COSMIC: COSV55108482;