21-46002725-A-G

Variant names:

• chr21-46002725-A-G
• rs2236485
• NM_001848.3:c.2434+15A>G

Variant summary

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

The ENST00000361866.8(COL6A1):​c.2434+15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.861 in 1,552,926 control chromosomes in the GnomAD database, including 576,881 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (57027 hom., cov: 35)
  • Exomes 𝑓: 0.86 (519854 hom.)
• Consequence: COL6A1 ENST00000361866.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.117
• Publications: 11 publications found

Genes affected

COL6A1 (HGNC:2211): (collagen type VI alpha 1 chain) The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix proteins and have a triple-helical domain as their common structural element. Collagen VI is a major structural component of microfibrils. The basic structural unit of collagen VI is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains. The alpha2(VI) and alpha3(VI) chains are encoded by the COL6A2 and COL6A3 genes, respectively. The protein encoded by this gene is the alpha 1 subunit of type VI collagen (alpha1(VI) chain). Mutations in the genes that code for the collagen VI subunits result in the autosomal dominant disorder, Bethlem myopathy. [provided by RefSeq, Jul 2008]

COL6A1 Gene-Disease associations (from GenCC):

• collagen 6-related myopathy

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

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AD, AR 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 21-46002725-A-G is Benign according to our data. Variant chr21-46002725-A-G is described in ClinVar as Benign. ClinVar VariationId is 93854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.9 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361866.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	NM_001848.3	MANE Select	c.2434+15A>G		intron	N/A	NP_001839.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	ENST00000361866.8	TSL:1 MANE Select	c.2434+15A>G		intron	N/A	ENSP00000355180.3
	COL6A1	ENST00000498614.5	TSL:1	n.668+15A>G		intron	N/A
	COL6A1	ENST00000612273.2	TSL:5	c.559+15A>G		intron	N/A	ENSP00000483630.2

Frequencies

GnomAD3 genomes AF: 0.873 AC: 130364 AN: 149364 Hom.: 56967 Cov.: 35

Gnomad AFR AF: 0.908

Gnomad AMI AF: 0.823

Gnomad AMR AF: 0.901

Gnomad ASJ AF: 0.805

Gnomad EAS AF: 0.868

Gnomad SAS AF: 0.784

Gnomad FIN AF: 0.884

Gnomad MID AF: 0.755

Gnomad NFE AF: 0.856

Gnomad OTH AF: 0.842

GnomAD2 exomes AF: 0.858 AC: 197631 AN: 230206 AF XY: 0.851

Gnomad AFR exome AF: 0.919

Gnomad AMR exome AF: 0.926

Gnomad ASJ exome AF: 0.815

Gnomad EAS exome AF: 0.854

Gnomad FIN exome AF: 0.880

Gnomad NFE exome AF: 0.852

Gnomad OTH exome AF: 0.858

GnomAD4 exome AF: 0.860 AC: 1206601 AN: 1403448 Hom.: 519854 Cov.: 51 AF XY: 0.857 AC XY: 599130 AN XY: 699274

African (AFR) AF: 0.919 AC: 29430 AN: 32038

American (AMR) AF: 0.923 AC: 39813 AN: 43118

Ashkenazi Jewish (ASJ) AF: 0.813 AC: 20871 AN: 25686

East Asian (EAS) AF: 0.878 AC: 34296 AN: 39072

South Asian (SAS) AF: 0.785 AC: 66121 AN: 84268

European-Finnish (FIN) AF: 0.888 AC: 44781 AN: 50442

Middle Eastern (MID) AF: 0.790 AC: 4340 AN: 5494

European-Non Finnish (NFE) AF: 0.861 AC: 917262 AN: 1065042

Other (OTH) AF: 0.852 AC: 49687 AN: 58288

GnomAD4 genome AF: 0.873 AC: 130478 AN: 149478 Hom.: 57027 Cov.: 35 AF XY: 0.872 AC XY: 63755 AN XY: 73082

African (AFR) AF: 0.908 AC: 36550 AN: 40240

American (AMR) AF: 0.901 AC: 13649 AN: 15152

Ashkenazi Jewish (ASJ) AF: 0.805 AC: 2775 AN: 3448

East Asian (EAS) AF: 0.867 AC: 4412 AN: 5086

South Asian (SAS) AF: 0.785 AC: 3745 AN: 4772

European-Finnish (FIN) AF: 0.884 AC: 9221 AN: 10432

Middle Eastern (MID) AF: 0.752 AC: 218 AN: 290

European-Non Finnish (NFE) AF: 0.856 AC: 57419 AN: 67082

Other (OTH) AF: 0.842 AC: 1743 AN: 2070

Alfa AF: 0.854 Hom.: 8177

Bravo AF: 0.887

Asia WGS AF: 0.805 AC: 2717 AN: 3372

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Bethlem myopathy 1A (2)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	not provided (1)
-	-	1	Ullrich congenital muscular dystrophy 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.4
DANN	Benign	0.24
PhyloP100		0.12
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: rs2236485; hg19: chr21-47422639;