rs148766287

Variant names:

• chr21-45984508-C-G
• rs148766287
• NM_001848.3:c.428+39C>G

Your query was ambiguous. Multiple possible variants found:

• chr21-45984508-C-G
• chr21-45984508-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001848.3(COL6A1):​c.428+39C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,588,504 control chromosomes in the GnomAD database, including 193 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (13 hom., cov: 35)
  • Exomes 𝑓: 0.013 (180 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.211
• Publications: 3 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=-0.86).
• BP6: Variant 21-45984508-C-G is Benign according to our data. Variant chr21-45984508-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00942 (1436/152370) while in subpopulation NFE AF = 0.0146 (995/68038). AF 95% confidence interval is 0.0139. There are 13 homozygotes in GnomAd4. There are 709 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR,AD gene

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.428+39C>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.428+39C>G		intron	N/A	ENSP00000355180.3	P12109
	COL6A1	ENST00000866134.1		c.428+39C>G		intron	N/A	ENSP00000536193.1

Frequencies

GnomAD3 genomes AF: 0.00945 AC: 1439 AN: 152252 Hom.: 13 Cov.: 35

Gnomad AFR AF: 0.00270

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.0189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.00907

GnomAD2 exomes AF: 0.0105 AC: 2439 AN: 233246 AF XY: 0.0105

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.00274

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0215

Gnomad NFE exome AF: 0.0172

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.0132 AC: 18981 AN: 1436134 Hom.: 180 Cov.: 30 AF XY: 0.0129 AC XY: 9204 AN XY: 715584

African (AFR) AF: 0.00214 AC: 71 AN: 33104

American (AMR) AF: 0.00271 AC: 121 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 75 AN: 26008

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39524

South Asian (SAS) AF: 0.00365 AC: 313 AN: 85656

European-Finnish (FIN) AF: 0.0209 AC: 878 AN: 41920

Middle Eastern (MID) AF: 0.00488 AC: 28 AN: 5738

European-Non Finnish (NFE) AF: 0.0154 AC: 16888 AN: 1099892

Other (OTH) AF: 0.0101 AC: 606 AN: 59708

GnomAD4 genome AF: 0.00942 AC: 1436 AN: 152370 Hom.: 13 Cov.: 35 AF XY: 0.00952 AC XY: 709 AN XY: 74506

African (AFR) AF: 0.00269 AC: 112 AN: 41582

American (AMR) AF: 0.00405 AC: 62 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4834

European-Finnish (FIN) AF: 0.0189 AC: 201 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0146 AC: 995 AN: 68038

Other (OTH) AF: 0.00898 AC: 19 AN: 2116

Alfa AF: 0.00539 Hom.: 2

Bravo AF: 0.00807

ClinVar

ClinVar submissions

Significance: Benign/Likely 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	-0.86
CADD	Benign	1.1
DANN	Benign	0.40
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism

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: rs148766287; hg19: chr21-47404422;