rs9977394

Variant names:

• chr21-46132216-A-G
• rs9977394
• NM_001849.4:c.2724A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001849.4(COL6A2):​c.2724A>G​(p.Thr908Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,592,298 control chromosomes in the GnomAD database, including 10,849 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1871 hom., cov: 34)
  • Exomes 𝑓: 0.10 (8978 hom.)
• Consequence: COL6A2 NM_001849.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.0370
• Publications: 8 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 21-46132216-A-G is Benign according to our data. Variant chr21-46132216-A-G is described in ClinVar as Benign. ClinVar VariationId is 93945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.037 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.254 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.2724A>G	p.Thr908Thr	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.2724A>G	p.Thr908Thr	synonymous	Exon 28 of 28	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000857098.1		c.2919A>G	p.Thr973Thr	synonymous	Exon 28 of 28	ENSP00000527157.1
	COL6A2	ENST00000857103.1		c.2886A>G	p.Thr962Thr	synonymous	Exon 28 of 28	ENSP00000527162.1

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20795 AN: 152062 Hom.: 1868 Cov.: 34

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.0714

Gnomad AMR AF: 0.0802

Gnomad ASJ AF: 0.0882

Gnomad EAS AF: 0.0254

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.0371

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.100

Gnomad OTH AF: 0.128

GnomAD2 exomes AF: 0.0984 AC: 20809 AN: 211458 AF XY: 0.102

Gnomad AFR exome AF: 0.259

Gnomad AMR exome AF: 0.0521

Gnomad ASJ exome AF: 0.0871

Gnomad EAS exome AF: 0.0247

Gnomad FIN exome AF: 0.0329

Gnomad NFE exome AF: 0.0960

Gnomad OTH exome AF: 0.0888

GnomAD4 exome AF: 0.104 AC: 149607 AN: 1440118 Hom.: 8978 Cov.: 35 AF XY: 0.105 AC XY: 75356 AN XY: 715164

African (AFR) AF: 0.265 AC: 8722 AN: 32886

American (AMR) AF: 0.0560 AC: 2351 AN: 41960

Ashkenazi Jewish (ASJ) AF: 0.0901 AC: 2318 AN: 25736

East Asian (EAS) AF: 0.0220 AC: 843 AN: 38300

South Asian (SAS) AF: 0.169 AC: 14205 AN: 83856

European-Finnish (FIN) AF: 0.0389 AC: 1921 AN: 49386

Middle Eastern (MID) AF: 0.127 AC: 727 AN: 5744

European-Non Finnish (NFE) AF: 0.102 AC: 112022 AN: 1102638

Other (OTH) AF: 0.109 AC: 6498 AN: 59612

GnomAD4 genome AF: 0.137 AC: 20844 AN: 152180 Hom.: 1871 Cov.: 34 AF XY: 0.133 AC XY: 9881 AN XY: 74414

African (AFR) AF: 0.258 AC: 10726 AN: 41494

American (AMR) AF: 0.0800 AC: 1223 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0882 AC: 306 AN: 3470

East Asian (EAS) AF: 0.0255 AC: 132 AN: 5176

South Asian (SAS) AF: 0.182 AC: 877 AN: 4824

European-Finnish (FIN) AF: 0.0371 AC: 394 AN: 10612

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

European-Non Finnish (NFE) AF: 0.100 AC: 6806 AN: 67996

Other (OTH) AF: 0.132 AC: 279 AN: 2114

Alfa AF: 0.109 Hom.: 383

Bravo AF: 0.144

Asia WGS AF: 0.144 AC: 504 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.27
DANN	Benign	0.28
PhyloP100		-0.037
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: rs9977394; hg19: chr21-47552130;