chr21-45997389-T-C

Variant names:

• chr21-45997389-T-C
• rs2839077
• NM_001848.3:c.1399-32T>C

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.1399-32T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.522 in 1,605,044 control chromosomes in the GnomAD database, including 222,502 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19486 hom., cov: 32)
  • Exomes 𝑓: 0.52 (203016 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.03
• Publications: 10 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=-0.93).
• BP6: Variant 21-45997389-T-C is Benign according to our data. Variant chr21-45997389-T-C is described in ClinVar as Benign. ClinVar VariationId is 93813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.649 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.1399-32T>C		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.1399-32T>C		intron	N/A	ENSP00000355180.3
	COL6A1	ENST00000683550.1		n.174-32T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.499 AC: 75679 AN: 151746 Hom.: 19465 Cov.: 32

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.562

Gnomad AMR AF: 0.641

Gnomad ASJ AF: 0.494

Gnomad EAS AF: 0.667

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.516

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.509

GnomAD2 exomes AF: 0.548 AC: 137059 AN: 250246 AF XY: 0.537

Gnomad AFR exome AF: 0.384

Gnomad AMR exome AF: 0.754

Gnomad ASJ exome AF: 0.499

Gnomad EAS exome AF: 0.674

Gnomad FIN exome AF: 0.511

Gnomad NFE exome AF: 0.522

Gnomad OTH exome AF: 0.538

GnomAD4 exome AF: 0.524 AC: 761770 AN: 1453180 Hom.: 203016 Cov.: 32 AF XY: 0.522 AC XY: 377565 AN XY: 723416

African (AFR) AF: 0.371 AC: 12356 AN: 33322

American (AMR) AF: 0.740 AC: 33059 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 12934 AN: 26086

East Asian (EAS) AF: 0.651 AC: 25827 AN: 39654

South Asian (SAS) AF: 0.469 AC: 40359 AN: 86134

European-Finnish (FIN) AF: 0.523 AC: 27362 AN: 52344

Middle Eastern (MID) AF: 0.471 AC: 2706 AN: 5750

European-Non Finnish (NFE) AF: 0.522 AC: 576560 AN: 1105084

Other (OTH) AF: 0.509 AC: 30607 AN: 60110

GnomAD4 genome AF: 0.499 AC: 75746 AN: 151864 Hom.: 19486 Cov.: 32 AF XY: 0.501 AC XY: 37143 AN XY: 74200

African (AFR) AF: 0.384 AC: 15881 AN: 41392

American (AMR) AF: 0.641 AC: 9798 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.494 AC: 1712 AN: 3468

East Asian (EAS) AF: 0.668 AC: 3415 AN: 5116

South Asian (SAS) AF: 0.469 AC: 2257 AN: 4810

European-Finnish (FIN) AF: 0.516 AC: 5460 AN: 10584

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.523 AC: 35486 AN: 67902

Other (OTH) AF: 0.513 AC: 1083 AN: 2110

Alfa AF: 0.520 Hom.: 72357

Bravo AF: 0.507

Asia WGS AF: 0.568 AC: 1974 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.65
DANN	Benign	0.48
PhyloP100		-1.0
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: rs2839077; hg19: chr21-47417303; COSMIC: COSV62612066; COSMIC: COSV62612066;