NM_001849.4:c.2979C>T

Variant names:

• chr21-46132471-C-T
• rs6652
• NM_001849.4:c.2979C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001849.4(COL6A2):​c.2979C>T​(p.Arg993Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 1,605,962 control chromosomes in the GnomAD database, including 26,910 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R993R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.14 (1768 hom., cov: 34)
  • Exomes 𝑓: 0.18 (25142 hom.)
• Consequence: COL6A2 NM_001849.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.00
• Publications: 13 publications found

Genes affected

COL6A2 (HGNC:2212): (collagen type VI alpha 2 chain) This gene encodes one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The product of this gene contains several domains similar to von Willebrand Factor type A domains. 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 this gene are associated with Bethlem myopathy and Ullrich scleroatonic muscular dystrophy. Three transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]

COL6A2 Gene-Disease associations (from GenCC):

• collagen 6-related myopathy

  Inheritance: AD, SD, AR Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1B

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: G2P
• Bethlem myopathy 1A

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AR, AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Bethlem myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ullrich congenital muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myosclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 21-46132471-C-T is Benign according to our data. Variant chr21-46132471-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001849.4. 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
	COL6A2	NM_001849.4	MANE Select	c.2979C>T	p.Arg993Arg	synonymous	Exon 28 of 28	NP_001840.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	ENST00000300527.9	TSL:1 MANE Select	c.2979C>T	p.Arg993Arg	synonymous	Exon 28 of 28	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000857098.1		c.3174C>T	p.Arg1058Arg	synonymous	Exon 28 of 28	ENSP00000527157.1
	COL6A2	ENST00000857103.1		c.3141C>T	p.Arg1047Arg	synonymous	Exon 28 of 28	ENSP00000527162.1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21579 AN: 152170 Hom.: 1770 Cov.: 34

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.0191

Gnomad SAS AF: 0.0765

Gnomad FIN AF: 0.0715

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.194

Gnomad OTH AF: 0.149

GnomAD2 exomes AF: 0.131 AC: 31507 AN: 239922 AF XY: 0.134

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.0741

Gnomad ASJ exome AF: 0.176

Gnomad EAS exome AF: 0.0244

Gnomad FIN exome AF: 0.0714

Gnomad NFE exome AF: 0.191

Gnomad OTH exome AF: 0.149

GnomAD4 exome AF: 0.177 AC: 257816 AN: 1453674 Hom.: 25142 Cov.: 36 AF XY: 0.174 AC XY: 126041 AN XY: 722692

African (AFR) AF: 0.104 AC: 3464 AN: 33398

American (AMR) AF: 0.0788 AC: 3511 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 4659 AN: 26056

East Asian (EAS) AF: 0.0218 AC: 863 AN: 39572

South Asian (SAS) AF: 0.0796 AC: 6859 AN: 86118

European-Finnish (FIN) AF: 0.0790 AC: 3867 AN: 48964

Middle Eastern (MID) AF: 0.156 AC: 898 AN: 5762

European-Non Finnish (NFE) AF: 0.202 AC: 223570 AN: 1109128

Other (OTH) AF: 0.168 AC: 10125 AN: 60116

GnomAD4 genome AF: 0.142 AC: 21578 AN: 152288 Hom.: 1768 Cov.: 34 AF XY: 0.133 AC XY: 9925 AN XY: 74468

African (AFR) AF: 0.109 AC: 4539 AN: 41566

American (AMR) AF: 0.104 AC: 1587 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 605 AN: 3470

East Asian (EAS) AF: 0.0191 AC: 99 AN: 5178

South Asian (SAS) AF: 0.0757 AC: 366 AN: 4832

European-Finnish (FIN) AF: 0.0715 AC: 760 AN: 10626

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.194 AC: 13204 AN: 67994

Other (OTH) AF: 0.147 AC: 312 AN: 2116

Alfa AF: 0.175 Hom.: 4130

Bravo AF: 0.144

Asia WGS AF: 0.0690 AC: 240 AN: 3478

EpiCase AF: 0.200

EpiControl AF: 0.196

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	Glutamate formiminotransferase deficiency (1)
-	-	1	Myosclerosis (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	7.6
DANN	Benign	0.92
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: rs6652; hg19: chr21-47552385; COSMIC: COSV52425432; COSMIC: COSV52425432;