chr2-237324109-C-A

Variant names:

• chr2-237324109-C-A
• rs1050785
• NM_004369.4:c.*665G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004369.4(COL6A3):​c.*665G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 149,242 control chromosomes in the GnomAD database, including 32,004 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (31946 hom., cov: 30)
  • Exomes 𝑓: 0.57 (58 hom.)
• Consequence: COL6A3 NM_004369.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.02
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-237324109-C-A is Benign according to our data. Variant chr2-237324109-C-A is described in ClinVar as Benign. ClinVar VariationId is 335089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.773 is higher than 0.05.

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.*665G>T		3_prime_UTR	Exon 44 of 44	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.*665G>T		3_prime_UTR	Exon 43 of 43	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.*665G>T		3_prime_UTR	Exon 41 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.*665G>T		3_prime_UTR	Exon 44 of 44	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.*665G>T		3_prime_UTR	Exon 41 of 41	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000952249.1		c.*665G>T		3_prime_UTR	Exon 41 of 41	ENSP00000622308.1

Frequencies

GnomAD3 genomes AF: 0.654 AC: 97230 AN: 148732 Hom.: 31915 Cov.: 30

Gnomad AFR AF: 0.781

Gnomad AMI AF: 0.609

Gnomad AMR AF: 0.649

Gnomad ASJ AF: 0.608

Gnomad EAS AF: 0.553

Gnomad SAS AF: 0.676

Gnomad FIN AF: 0.588

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.596

Gnomad OTH AF: 0.655

GnomAD4 exome AF: 0.574 AC: 240 AN: 418 Hom.: 58 Cov.: 0 AF XY: 0.571 AC XY: 144 AN XY: 252

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.576 AC: 234 AN: 406

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 4 AN: 8

Other (OTH) AF: 0.500 AC: 2 AN: 4

GnomAD4 genome AF: 0.654 AC: 97314 AN: 148824 Hom.: 31946 Cov.: 30 AF XY: 0.652 AC XY: 47274 AN XY: 72498

African (AFR) AF: 0.781 AC: 31791 AN: 40728

American (AMR) AF: 0.650 AC: 9773 AN: 15040

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 2064 AN: 3394

East Asian (EAS) AF: 0.553 AC: 2844 AN: 5140

South Asian (SAS) AF: 0.675 AC: 3207 AN: 4750

European-Finnish (FIN) AF: 0.588 AC: 5637 AN: 9588

Middle Eastern (MID) AF: 0.630 AC: 179 AN: 284

European-Non Finnish (NFE) AF: 0.596 AC: 39931 AN: 66956

Other (OTH) AF: 0.656 AC: 1340 AN: 2044

Alfa AF: 0.606 Hom.: 43249

Bravo AF: 0.657

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Collagen 6-related myopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.8
DANN	Benign	0.32
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs1050785; hg19: chr2-238232752;