rs201814201

Variant names:

• chr2-237354908-G-A
• rs201814201
• NM_004369.4:c.6618C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-237354908-G-A
• chr2-237354908-G-C
• chr2-237354908-G-T

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.6618C>T​(p.Pro2206Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000573 in 1,612,006 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (10 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.72
• 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: 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 2-237354908-G-A is Benign according to our data. Variant chr2-237354908-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 281259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.72 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000499 (76/152250) while in subpopulation SAS AF = 0.00643 (31/4820). AF 95% confidence interval is 0.00466. There are 0 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 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.6618C>T	p.Pro2206Pro	synonymous	Exon 24 of 44	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.6000C>T	p.Pro2000Pro	synonymous	Exon 23 of 43	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.4797C>T	p.Pro1599Pro	synonymous	Exon 21 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.6618C>T	p.Pro2206Pro	synonymous	Exon 24 of 44	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.4797C>T	p.Pro1599Pro	synonymous	Exon 21 of 41	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000353578.9	TSL:5	c.6000C>T	p.Pro2000Pro	synonymous	Exon 23 of 43	ENSP00000315873.4	P12111-2

Frequencies

GnomAD3 genomes AF: 0.000500 AC: 76 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00643

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.00108 AC: 268 AN: 248992 AF XY: 0.00140

Gnomad AFR exome AF: 0.0000627

Gnomad AMR exome AF: 0.000495

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000284

Gnomad OTH exome AF: 0.000658

GnomAD4 exome AF: 0.000580 AC: 847 AN: 1459756 Hom.: 10 Cov.: 30 AF XY: 0.000795 AC XY: 577 AN XY: 726188

African (AFR) AF: 0.0000299 AC: 1 AN: 33434

American (AMR) AF: 0.000627 AC: 28 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.000997 AC: 26 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00665 AC: 571 AN: 85898

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53314

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5756

European-Non Finnish (NFE) AF: 0.000161 AC: 179 AN: 1110676

Other (OTH) AF: 0.000547 AC: 33 AN: 60332

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74444

African (AFR) AF: 0.000120 AC: 5 AN: 41544

American (AMR) AF: 0.00111 AC: 17 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00643 AC: 31 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68014

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.000467 Hom.: 0

Bravo AF: 0.000431

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000328

EpiControl AF: 0.000416

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.069
DANN	Benign	0.78
PhyloP100		-2.7
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201814201; hg19: chr2-238263551; COSMIC: COSV55080904; COSMIC: COSV55080904;