21-46132189-G-T

Variant names:

• chr21-46132189-G-T
• rs11554669
• NM_001849.4:c.2697G>T

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.2697G>T​(p.Thr899Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0407 in 1,575,690 control chromosomes in the GnomAD database, including 1,497 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. T899T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.028 (89 hom., cov: 34)
  • Exomes 𝑓: 0.042 (1408 hom.)
• Consequence: COL6A2 NM_001849.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -4.97
• Publications: 11 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=-0.9).
• BP6: Variant 21-46132189-G-T is Benign according to our data. Variant chr21-46132189-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.97 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0535 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.2697G>T	p.Thr899Thr	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.2697G>T	p.Thr899Thr	synonymous	Exon 28 of 28	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000857098.1		c.2892G>T	p.Thr964Thr	synonymous	Exon 28 of 28	ENSP00000527157.1
	COL6A2	ENST00000857103.1		c.2859G>T	p.Thr953Thr	synonymous	Exon 28 of 28	ENSP00000527162.1

Frequencies

GnomAD3 genomes AF: 0.0282 AC: 4292 AN: 152182 Hom.: 89 Cov.: 34

Gnomad AFR AF: 0.00755

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0266

Gnomad ASJ AF: 0.0306

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0447

Gnomad FIN AF: 0.0263

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0427

Gnomad OTH AF: 0.0205

GnomAD2 exomes AF: 0.0342 AC: 6339 AN: 185290 AF XY: 0.0367

Gnomad AFR exome AF: 0.00635

Gnomad AMR exome AF: 0.0230

Gnomad ASJ exome AF: 0.0316

Gnomad EAS exome AF: 0.000230

Gnomad FIN exome AF: 0.0268

Gnomad NFE exome AF: 0.0429

Gnomad OTH exome AF: 0.0360

GnomAD4 exome AF: 0.0421 AC: 59891 AN: 1423390 Hom.: 1408 Cov.: 34 AF XY: 0.0424 AC XY: 29916 AN XY: 705294

African (AFR) AF: 0.00657 AC: 213 AN: 32418

American (AMR) AF: 0.0233 AC: 909 AN: 39016

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 792 AN: 25474

East Asian (EAS) AF: 0.0000539 AC: 2 AN: 37080

South Asian (SAS) AF: 0.0548 AC: 4512 AN: 82284

European-Finnish (FIN) AF: 0.0276 AC: 1337 AN: 48530

Middle Eastern (MID) AF: 0.0306 AC: 175 AN: 5726

European-Non Finnish (NFE) AF: 0.0455 AC: 49754 AN: 1093890

Other (OTH) AF: 0.0373 AC: 2197 AN: 58972

GnomAD4 genome AF: 0.0281 AC: 4287 AN: 152300 Hom.: 89 Cov.: 34 AF XY: 0.0275 AC XY: 2046 AN XY: 74468

African (AFR) AF: 0.00753 AC: 313 AN: 41574

American (AMR) AF: 0.0265 AC: 406 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0306 AC: 106 AN: 3468

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5186

South Asian (SAS) AF: 0.0446 AC: 215 AN: 4826

European-Finnish (FIN) AF: 0.0263 AC: 279 AN: 10614

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0427 AC: 2903 AN: 68008

Other (OTH) AF: 0.0203 AC: 43 AN: 2116

Alfa AF: 0.0170 Hom.: 13

Bravo AF: 0.0266

Asia WGS AF: 0.0230 AC: 81 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely 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	-0.90
CADD	Benign	0.094
DANN	Benign	0.88
PhyloP100		-5.0
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: rs11554669; hg19: chr21-47552103; COSMIC: COSV99039003; COSMIC: COSV99039003;