NM_001849.4:c.714+9C>T

Variant names:

• chr21-46112586-C-T
• rs78822624
• NM_001849.4:c.714+9C>T

Variant summary

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

The NM_001849.4(COL6A2):​c.714+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0468 in 1,611,360 control chromosomes in the GnomAD database, including 2,028 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (133 hom., cov: 32)
  • Exomes 𝑓: 0.048 (1895 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.558
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 21-46112586-C-T is Benign according to our data. Variant chr21-46112586-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0516 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.714+9C>T		intron	N/A	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.714+9C>T		intron	N/A	NP_478054.2	P12110-2
	COL6A2	NM_058175.3		c.714+9C>T		intron	N/A	NP_478055.2	P12110-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	ENST00000300527.9	TSL:1 MANE Select	c.714+9C>T		intron	N/A	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.714+9C>T		intron	N/A	ENSP00000380870.1	P12110-2
	COL6A2	ENST00000857098.1		c.714+9C>T		intron	N/A	ENSP00000527157.1

Frequencies

GnomAD3 genomes AF: 0.0351 AC: 5330 AN: 151990 Hom.: 133 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.0540

Gnomad AMR AF: 0.0185

Gnomad ASJ AF: 0.0332

Gnomad EAS AF: 0.000971

Gnomad SAS AF: 0.0255

Gnomad FIN AF: 0.0623

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.0530

Gnomad OTH AF: 0.0273

GnomAD2 exomes AF: 0.0384 AC: 9347 AN: 243458 AF XY: 0.0400

Gnomad AFR exome AF: 0.00927

Gnomad AMR exome AF: 0.0155

Gnomad ASJ exome AF: 0.0316

Gnomad EAS exome AF: 0.000219

Gnomad FIN exome AF: 0.0715

Gnomad NFE exome AF: 0.0532

Gnomad OTH exome AF: 0.0342

GnomAD4 exome AF: 0.0481 AC: 70154 AN: 1459252 Hom.: 1895 Cov.: 34 AF XY: 0.0477 AC XY: 34645 AN XY: 725936

African (AFR) AF: 0.00882 AC: 295 AN: 33454

American (AMR) AF: 0.0157 AC: 701 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 811 AN: 26110

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39686

South Asian (SAS) AF: 0.0315 AC: 2715 AN: 86234

European-Finnish (FIN) AF: 0.0715 AC: 3678 AN: 51422

Middle Eastern (MID) AF: 0.0460 AC: 264 AN: 5740

European-Non Finnish (NFE) AF: 0.0533 AC: 59262 AN: 1111578

Other (OTH) AF: 0.0401 AC: 2422 AN: 60332

GnomAD4 genome AF: 0.0350 AC: 5327 AN: 152108 Hom.: 133 Cov.: 32 AF XY: 0.0351 AC XY: 2610 AN XY: 74380

African (AFR) AF: 0.0100 AC: 417 AN: 41512

American (AMR) AF: 0.0184 AC: 281 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0332 AC: 115 AN: 3466

East Asian (EAS) AF: 0.000974 AC: 5 AN: 5136

South Asian (SAS) AF: 0.0261 AC: 126 AN: 4822

European-Finnish (FIN) AF: 0.0623 AC: 661 AN: 10602

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.0530 AC: 3602 AN: 67966

Other (OTH) AF: 0.0270 AC: 57 AN: 2110

Alfa AF: 0.0486 Hom.: 290

Bravo AF: 0.0300

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	Myosclerosis (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.7
DANN	Benign	0.94
PhyloP100		0.56
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs78822624; hg19: chr21-47532500;