21-46000812-C-G

Variant names:

• chr21-46000812-C-G
• rs7276098
• NM_001848.3:c.1822+45C>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.1822+45C>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 1,610,990 control chromosomes in the GnomAD database, including 589,706 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (54298 hom., cov: 36)
  • Exomes 𝑓: 0.86 (535408 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.133
• Publications: 11 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 21-46000812-C-G is Benign according to our data. Variant chr21-46000812-C-G is described in ClinVar as Benign. ClinVar VariationId is 93832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.877 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.1822+45C>G		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.1822+45C>G		intron	N/A	ENSP00000355180.3	P12109
	COL6A1	ENST00000866134.1		c.565-1715C>G		intron	N/A	ENSP00000536193.1
	COL6A1	ENST00000466285.1	TSL:3	n.384C>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.844 AC: 128366 AN: 152148 Hom.: 54253 Cov.: 36

Gnomad AFR AF: 0.802

Gnomad AMI AF: 0.827

Gnomad AMR AF: 0.889

Gnomad ASJ AF: 0.798

Gnomad EAS AF: 0.873

Gnomad SAS AF: 0.785

Gnomad FIN AF: 0.886

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.858

Gnomad OTH AF: 0.820

GnomAD2 exomes AF: 0.854 AC: 214197 AN: 250872 AF XY: 0.849

Gnomad AFR exome AF: 0.800

Gnomad AMR exome AF: 0.919

Gnomad ASJ exome AF: 0.809

Gnomad EAS exome AF: 0.859

Gnomad FIN exome AF: 0.885

Gnomad NFE exome AF: 0.858

Gnomad OTH exome AF: 0.853

GnomAD4 exome AF: 0.856 AC: 1248815 AN: 1458724 Hom.: 535408 Cov.: 37 AF XY: 0.853 AC XY: 619474 AN XY: 725838

African (AFR) AF: 0.800 AC: 26726 AN: 33422

American (AMR) AF: 0.914 AC: 40880 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.804 AC: 20983 AN: 26114

East Asian (EAS) AF: 0.880 AC: 34918 AN: 39682

South Asian (SAS) AF: 0.788 AC: 67926 AN: 86200

European-Finnish (FIN) AF: 0.890 AC: 47168 AN: 53024

Middle Eastern (MID) AF: 0.774 AC: 4455 AN: 5758

European-Non Finnish (NFE) AF: 0.861 AC: 955003 AN: 1109524

Other (OTH) AF: 0.842 AC: 50756 AN: 60288

GnomAD4 genome AF: 0.844 AC: 128464 AN: 152266 Hom.: 54298 Cov.: 36 AF XY: 0.846 AC XY: 62964 AN XY: 74444

African (AFR) AF: 0.802 AC: 33312 AN: 41552

American (AMR) AF: 0.890 AC: 13617 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.798 AC: 2769 AN: 3470

East Asian (EAS) AF: 0.873 AC: 4518 AN: 5176

South Asian (SAS) AF: 0.786 AC: 3798 AN: 4830

European-Finnish (FIN) AF: 0.886 AC: 9411 AN: 10620

Middle Eastern (MID) AF: 0.714 AC: 210 AN: 294

European-Non Finnish (NFE) AF: 0.858 AC: 58342 AN: 67994

Other (OTH) AF: 0.820 AC: 1733 AN: 2114

Alfa AF: 0.844 Hom.: 5776

Bravo AF: 0.875

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.4
DANN	Benign	0.40
PhyloP100		-0.13
PromoterAI		-0.046	Neutral
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: rs7276098; hg19: chr21-47420726;