21-45989589-A-G

Variant names:

• chr21-45989589-A-G
• rs2277814
• NM_001848.3:c.859-19A>G

Variant summary

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

The NM_001848.3(COL6A1):​c.859-19A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.855 in 1,611,554 control chromosomes in the GnomAD database, including 589,168 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (57254 hom., cov: 33)
  • Exomes 𝑓: 0.85 (531914 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -3.27
• Publications: 16 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=-0.92).
• BP6: Variant 21-45989589-A-G is Benign according to our data. Variant chr21-45989589-A-G is described in ClinVar as Benign. ClinVar VariationId is 93891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.904 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.859-19A>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.859-19A>G		intron	N/A	ENSP00000355180.3

Frequencies

GnomAD3 genomes AF: 0.868 AC: 131902 AN: 151966 Hom.: 57210 Cov.: 33

Gnomad AFR AF: 0.887

Gnomad AMI AF: 0.865

Gnomad AMR AF: 0.862

Gnomad ASJ AF: 0.838

Gnomad EAS AF: 0.926

Gnomad SAS AF: 0.851

Gnomad FIN AF: 0.887

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.853

Gnomad OTH AF: 0.880

GnomAD2 exomes AF: 0.859 AC: 214735 AN: 250032 AF XY: 0.858

Gnomad AFR exome AF: 0.886

Gnomad AMR exome AF: 0.831

Gnomad ASJ exome AF: 0.827

Gnomad EAS exome AF: 0.926

Gnomad FIN exome AF: 0.880

Gnomad NFE exome AF: 0.855

Gnomad OTH exome AF: 0.859

GnomAD4 exome AF: 0.853 AC: 1245414 AN: 1459472 Hom.: 531914 Cov.: 47 AF XY: 0.853 AC XY: 619391 AN XY: 726058

African (AFR) AF: 0.883 AC: 29514 AN: 33434

American (AMR) AF: 0.836 AC: 37394 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.832 AC: 21734 AN: 26130

East Asian (EAS) AF: 0.933 AC: 37029 AN: 39694

South Asian (SAS) AF: 0.846 AC: 72908 AN: 86222

European-Finnish (FIN) AF: 0.881 AC: 45953 AN: 52152

Middle Eastern (MID) AF: 0.860 AC: 4779 AN: 5556

European-Non Finnish (NFE) AF: 0.850 AC: 944433 AN: 1111258

Other (OTH) AF: 0.857 AC: 51670 AN: 60310

GnomAD4 genome AF: 0.868 AC: 132005 AN: 152082 Hom.: 57254 Cov.: 33 AF XY: 0.868 AC XY: 64518 AN XY: 74348

African (AFR) AF: 0.886 AC: 36751 AN: 41460

American (AMR) AF: 0.862 AC: 13198 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.838 AC: 2908 AN: 3470

East Asian (EAS) AF: 0.926 AC: 4770 AN: 5150

South Asian (SAS) AF: 0.851 AC: 4106 AN: 4824

European-Finnish (FIN) AF: 0.887 AC: 9405 AN: 10608

Middle Eastern (MID) AF: 0.898 AC: 264 AN: 294

European-Non Finnish (NFE) AF: 0.853 AC: 57956 AN: 67946

Other (OTH) AF: 0.881 AC: 1858 AN: 2108

Alfa AF: 0.858 Hom.: 195261

Bravo AF: 0.869

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 14, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 22, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Bethlem myopathy 1A Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ullrich congenital muscular dystrophy 1A Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0020
DANN	Benign	0.39
PhyloP100		-3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2277814; hg19: chr21-47409503;