rs200245740

Variant names:

• chr21-45999004-C-CCA
• rs200245740
• NM_001848.3:c.1674+46_1674+47dupCA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001848.3(COL6A1):​c.1674+46_1674+47dupCA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00394 in 1,548,928 control chromosomes in the GnomAD database, including 71 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (34 hom., cov: 34)
  • Exomes 𝑓: 0.0030 (37 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.72
• Publications: 0 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 -10 ACMG points.

• BP6: Variant 21-45999004-C-CCA is Benign according to our data. Variant chr21-45999004-C-CCA is described in ClinVar as Benign. ClinVar VariationId is 258292.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0128 (1954/152280) while in subpopulation AFR AF = 0.0378 (1571/41556). AF 95% confidence interval is 0.0362. There are 34 homozygotes in GnomAd4. There are 957 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 AR,AD gene

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.1674+46_1674+47dupCA		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.1674+45_1674+46insCA		intron	N/A	ENSP00000355180.3

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1936 AN: 152162 Hom.: 30 Cov.: 34

Gnomad AFR AF: 0.0375

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00688

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00282

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00446 AC: 692 AN: 155114 AF XY: 0.00371

Gnomad AFR exome AF: 0.0421

Gnomad AMR exome AF: 0.00219

Gnomad ASJ exome AF: 0.00272

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00801

Gnomad NFE exome AF: 0.00201

Gnomad OTH exome AF: 0.00273

GnomAD4 exome AF: 0.00297 AC: 4147 AN: 1396648 Hom.: 37 Cov.: 32 AF XY: 0.00277 AC XY: 1907 AN XY: 688724

African (AFR) AF: 0.0414 AC: 1310 AN: 31638

American (AMR) AF: 0.00272 AC: 97 AN: 35684

Ashkenazi Jewish (ASJ) AF: 0.00227 AC: 57 AN: 25158

East Asian (EAS) AF: 0.0000279 AC: 1 AN: 35830

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79212

European-Finnish (FIN) AF: 0.00617 AC: 297 AN: 48132

Middle Eastern (MID) AF: 0.00424 AC: 24 AN: 5662

European-Non Finnish (NFE) AF: 0.00191 AC: 2056 AN: 1077404

Other (OTH) AF: 0.00521 AC: 302 AN: 57928

GnomAD4 genome AF: 0.0128 AC: 1954 AN: 152280 Hom.: 34 Cov.: 34 AF XY: 0.0129 AC XY: 957 AN XY: 74470

African (AFR) AF: 0.0378 AC: 1571 AN: 41556

American (AMR) AF: 0.00530 AC: 81 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00688 AC: 73 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00282 AC: 192 AN: 68020

Other (OTH) AF: 0.0123 AC: 26 AN: 2116

Alfa AF: 0.00829 Hom.: 2

Bravo AF: 0.0138

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200245740; hg19: chr21-47418918;