21-45994015-G-T

Variant names:

• chr21-45994015-G-T
• rs2850174
• NM_001848.3:c.1336-152G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000361866.8(COL6A1):​c.1336-152G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.772 in 804,036 control chromosomes in the GnomAD database, including 240,520 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.78 (46409 hom., cov: 33)
  • Exomes 𝑓: 0.77 (194111 hom.)
• Consequence: COL6A1 ENST00000361866.8 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.20
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 21-45994015-G-T is Benign according to our data. Variant chr21-45994015-G-T is described in ClinVar as Benign. ClinVar VariationId is 679939.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.849 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.1336-152G>T		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.1336-152G>T		intron	N/A	ENSP00000355180.3
	COL6A1	ENST00000683550.1		n.-42G>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.779 AC: 118486 AN: 152046 Hom.: 46365 Cov.: 33

Gnomad AFR AF: 0.808

Gnomad AMI AF: 0.765

Gnomad AMR AF: 0.819

Gnomad ASJ AF: 0.738

Gnomad EAS AF: 0.871

Gnomad SAS AF: 0.763

Gnomad FIN AF: 0.804

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.747

Gnomad OTH AF: 0.750

GnomAD4 exome AF: 0.770 AC: 501861 AN: 651872 Hom.: 194111 AF XY: 0.768 AC XY: 263080 AN XY: 342512

African (AFR) AF: 0.810 AC: 13987 AN: 17260

American (AMR) AF: 0.871 AC: 29472 AN: 33830

Ashkenazi Jewish (ASJ) AF: 0.752 AC: 14914 AN: 19830

East Asian (EAS) AF: 0.880 AC: 28186 AN: 32044

South Asian (SAS) AF: 0.761 AC: 48149 AN: 63242

European-Finnish (FIN) AF: 0.811 AC: 37476 AN: 46194

Middle Eastern (MID) AF: 0.716 AC: 1968 AN: 2750

European-Non Finnish (NFE) AF: 0.749 AC: 302326 AN: 403592

Other (OTH) AF: 0.766 AC: 25383 AN: 33130

GnomAD4 genome AF: 0.779 AC: 118578 AN: 152164 Hom.: 46409 Cov.: 33 AF XY: 0.782 AC XY: 58137 AN XY: 74390

African (AFR) AF: 0.807 AC: 33529 AN: 41542

American (AMR) AF: 0.819 AC: 12531 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.738 AC: 2560 AN: 3468

East Asian (EAS) AF: 0.871 AC: 4478 AN: 5144

South Asian (SAS) AF: 0.764 AC: 3686 AN: 4822

European-Finnish (FIN) AF: 0.804 AC: 8525 AN: 10604

Middle Eastern (MID) AF: 0.670 AC: 197 AN: 294

European-Non Finnish (NFE) AF: 0.747 AC: 50788 AN: 67970

Other (OTH) AF: 0.751 AC: 1589 AN: 2116

Alfa AF: 0.757 Hom.: 52405

Bravo AF: 0.783

Asia WGS AF: 0.801 AC: 2785 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.16
DANN	Benign	0.90
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2850174; hg19: chr21-47413929; COSMIC: COSV62616219;