21-46124855-A-G

Variant names:

• chr21-46124855-A-G
• rs73382466
• NM_001849.4:c.1735-30A>G

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.1735-30A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0891 in 1,612,104 control chromosomes in the GnomAD database, including 6,722 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (585 hom., cov: 33)
  • Exomes 𝑓: 0.089 (6137 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.358
• 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, 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: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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=-0.92).
• BP6: Variant 21-46124855-A-G is Benign according to our data. Variant chr21-46124855-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0973 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.1735-30A>G		intron	N/A	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.1735-30A>G		intron	N/A	NP_478054.2
	COL6A2	NM_058175.3		c.1735-30A>G		intron	N/A	NP_478055.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	ENST00000300527.9	TSL:1 MANE Select	c.1735-30A>G		intron	N/A	ENSP00000300527.4
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.1735-30A>G		intron	N/A	ENSP00000380870.1
	COL6A2	ENST00000857098.1		c.1930-30A>G		intron	N/A	ENSP00000527157.1

Frequencies

GnomAD3 genomes AF: 0.0897 AC: 13645 AN: 152086 Hom.: 584 Cov.: 33

Gnomad AFR AF: 0.0997

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.0938

Gnomad ASJ AF: 0.0789

Gnomad EAS AF: 0.0559

Gnomad SAS AF: 0.0524

Gnomad FIN AF: 0.0836

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0889

Gnomad OTH AF: 0.100

GnomAD2 exomes AF: 0.0825 AC: 20628 AN: 250142 AF XY: 0.0821

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.0765

Gnomad ASJ exome AF: 0.0776

Gnomad EAS exome AF: 0.0600

Gnomad FIN exome AF: 0.0828

Gnomad NFE exome AF: 0.0909

Gnomad OTH exome AF: 0.0800

GnomAD4 exome AF: 0.0891 AC: 130046 AN: 1459900 Hom.: 6137 Cov.: 35 AF XY: 0.0884 AC XY: 64203 AN XY: 726268

African (AFR) AF: 0.107 AC: 3597 AN: 33474

American (AMR) AF: 0.0782 AC: 3498 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0790 AC: 2063 AN: 26128

East Asian (EAS) AF: 0.0433 AC: 1718 AN: 39694

South Asian (SAS) AF: 0.0627 AC: 5412 AN: 86248

European-Finnish (FIN) AF: 0.0860 AC: 4489 AN: 52196

Middle Eastern (MID) AF: 0.0940 AC: 542 AN: 5766

European-Non Finnish (NFE) AF: 0.0931 AC: 103504 AN: 1111334

Other (OTH) AF: 0.0865 AC: 5223 AN: 60348

GnomAD4 genome AF: 0.0898 AC: 13661 AN: 152204 Hom.: 585 Cov.: 33 AF XY: 0.0886 AC XY: 6594 AN XY: 74440

African (AFR) AF: 0.0999 AC: 4144 AN: 41500

American (AMR) AF: 0.0937 AC: 1434 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0789 AC: 274 AN: 3472

East Asian (EAS) AF: 0.0559 AC: 289 AN: 5174

South Asian (SAS) AF: 0.0520 AC: 251 AN: 4826

European-Finnish (FIN) AF: 0.0836 AC: 887 AN: 10610

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0889 AC: 6042 AN: 68000

Other (OTH) AF: 0.100 AC: 212 AN: 2114

Alfa AF: 0.0872 Hom.: 117

Bravo AF: 0.0926

Asia WGS AF: 0.0600 AC: 210 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.098
DANN	Benign	0.19
PhyloP100		-0.36
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: rs73382466; hg19: chr21-47544769; COSMIC: COSV56006064;