rs3216137

Variant names:

• chr21-45997518-A-AG
• rs3216137
• NM_001848.3:c.1461+41dupG

Your query was ambiguous. Multiple possible variants found:

• chr21-45997518-A-AG
• chr21-45997518-A-AGG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001848.3(COL6A1):​c.1461+41dupG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.744 in 1,574,486 control chromosomes in the GnomAD database, including 433,533 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (41194 hom., cov: 0)
  • Exomes 𝑓: 0.74 (392339 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.134
• Publications: 6 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 -16 ACMG points.

• BP6: Variant 21-45997518-A-AG is Benign according to our data. Variant chr21-45997518-A-AG is described in ClinVar as Benign. ClinVar VariationId is 93816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.776 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001848.3. 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.1461+41dupG		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.1461+35_1461+36insG		intron	N/A	ENSP00000355180.3
	COL6A1	ENST00000683550.1		n.236+35_236+36insG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.737 AC: 111356 AN: 151074 Hom.: 41155 Cov.: 0

Gnomad AFR AF: 0.692

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.787

Gnomad ASJ AF: 0.742

Gnomad EAS AF: 0.745

Gnomad SAS AF: 0.684

Gnomad FIN AF: 0.811

Gnomad MID AF: 0.660

Gnomad NFE AF: 0.745

Gnomad OTH AF: 0.727

GnomAD2 exomes AF: 0.754 AC: 183575 AN: 243492 AF XY: 0.746

Gnomad AFR exome AF: 0.695

Gnomad AMR exome AF: 0.868

Gnomad ASJ exome AF: 0.752

Gnomad EAS exome AF: 0.730

Gnomad FIN exome AF: 0.811

Gnomad NFE exome AF: 0.744

Gnomad OTH exome AF: 0.757

GnomAD4 exome AF: 0.744 AC: 1059363 AN: 1423294 Hom.: 392339 Cov.: 31 AF XY: 0.742 AC XY: 526677 AN XY: 709912

African (AFR) AF: 0.695 AC: 22550 AN: 32466

American (AMR) AF: 0.861 AC: 38257 AN: 44424

Ashkenazi Jewish (ASJ) AF: 0.751 AC: 19242 AN: 25614

East Asian (EAS) AF: 0.730 AC: 28255 AN: 38696

South Asian (SAS) AF: 0.668 AC: 57050 AN: 85414

European-Finnish (FIN) AF: 0.820 AC: 41984 AN: 51216

Middle Eastern (MID) AF: 0.688 AC: 3858 AN: 5608

European-Non Finnish (NFE) AF: 0.744 AC: 804347 AN: 1081120

Other (OTH) AF: 0.746 AC: 43820 AN: 58736

GnomAD4 genome AF: 0.737 AC: 111446 AN: 151192 Hom.: 41194 Cov.: 0 AF XY: 0.739 AC XY: 54547 AN XY: 73846

African (AFR) AF: 0.692 AC: 28514 AN: 41194

American (AMR) AF: 0.788 AC: 12021 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.742 AC: 2567 AN: 3460

East Asian (EAS) AF: 0.745 AC: 3754 AN: 5040

South Asian (SAS) AF: 0.684 AC: 3203 AN: 4682

European-Finnish (FIN) AF: 0.811 AC: 8537 AN: 10524

Middle Eastern (MID) AF: 0.654 AC: 191 AN: 292

European-Non Finnish (NFE) AF: 0.745 AC: 50434 AN: 67722

Other (OTH) AF: 0.726 AC: 1529 AN: 2106

Alfa AF: 0.717 Hom.: 4007

Asia WGS AF: 0.709 AC: 2465 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.13
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: rs3216137; hg19: chr21-47417432; COSMIC: COSV107450281; COSMIC: COSV107450281;