21-45997781-G-C

Variant names:

• chr21-45997781-G-C
• rs2276256
• NM_001848.3:c.1524+19G>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.1524+19G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0868 in 1,569,514 control chromosomes in the GnomAD database, including 6,576 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.087 (639 hom., cov: 35)
  • Exomes 𝑓: 0.087 (5937 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.15
• Publications: 5 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):

• Bethlem myopathy 1A

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P
• collagen 6-related myopathy

  Inheritance: SD, AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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=-0.91).
• BP6: Variant 21-45997781-G-C is Benign according to our data. Variant chr21-45997781-G-C is described in ClinVar as Benign. ClinVar VariationId is 93821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.189 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	NM_001848.3	MANE Select	c.1524+19G>C		intron	N/A	NP_001839.2	P12109

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	ENST00000361866.8	TSL:1 MANE Select	c.1524+19G>C		intron	N/A	ENSP00000355180.3	P12109
	COL6A1	ENST00000866134.1		c.565-4746G>C		intron	N/A	ENSP00000536193.1
	COL6A1	ENST00000683550.1		n.299+19G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0865 AC: 13161 AN: 152090 Hom.: 635 Cov.: 35

Gnomad AFR AF: 0.0588

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.0729

Gnomad EAS AF: 0.198

Gnomad SAS AF: 0.0743

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0825

Gnomad OTH AF: 0.0970

GnomAD2 exomes AF: 0.101 AC: 17918 AN: 177312 AF XY: 0.0970

Gnomad AFR exome AF: 0.0604

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.0656

Gnomad EAS exome AF: 0.201

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.0840

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.0869 AC: 123101 AN: 1417306 Hom.: 5937 Cov.: 35 AF XY: 0.0863 AC XY: 60507 AN XY: 701214

African (AFR) AF: 0.0554 AC: 1800 AN: 32472

American (AMR) AF: 0.143 AC: 5546 AN: 38832

Ashkenazi Jewish (ASJ) AF: 0.0647 AC: 1643 AN: 25382

East Asian (EAS) AF: 0.209 AC: 7828 AN: 37392

South Asian (SAS) AF: 0.0704 AC: 5698 AN: 80984

European-Finnish (FIN) AF: 0.103 AC: 5075 AN: 49324

Middle Eastern (MID) AF: 0.104 AC: 492 AN: 4714

European-Non Finnish (NFE) AF: 0.0824 AC: 89773 AN: 1089600

Other (OTH) AF: 0.0895 AC: 5246 AN: 58606

GnomAD4 genome AF: 0.0866 AC: 13177 AN: 152208 Hom.: 639 Cov.: 35 AF XY: 0.0876 AC XY: 6519 AN XY: 74402

African (AFR) AF: 0.0587 AC: 2440 AN: 41556

American (AMR) AF: 0.129 AC: 1971 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0729 AC: 253 AN: 3472

East Asian (EAS) AF: 0.199 AC: 1023 AN: 5148

South Asian (SAS) AF: 0.0745 AC: 360 AN: 4830

European-Finnish (FIN) AF: 0.107 AC: 1133 AN: 10616

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0826 AC: 5611 AN: 67958

Other (OTH) AF: 0.100 AC: 212 AN: 2114

Alfa AF: 0.0432 Hom.: 45

Bravo AF: 0.0883

Asia WGS AF: 0.155 AC: 539 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.010
DANN	Benign	0.34
PhyloP100		-1.2
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: rs2276256; hg19: chr21-47417695; COSMIC: COSV62612072; COSMIC: COSV62612072;