rs754507

Variant names:

• chr21-45986698-C-A
• rs754507
• NM_001848.3:c.588+13C>A

Your query was ambiguous. Multiple possible variants found:

• chr21-45986698-C-A
• chr21-45986698-C-T

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.588+13C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.749 in 1,543,586 control chromosomes in the GnomAD database, including 436,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (38410 hom., cov: 31)
  • Exomes 𝑓: 0.75 (398163 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.155
• Publications: 13 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=-0.78).
• BP6: Variant 21-45986698-C-A is Benign according to our data. Variant chr21-45986698-C-A is described in ClinVar as Benign. ClinVar VariationId is 93879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.761 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.588+13C>A		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.588+13C>A		intron	N/A	ENSP00000355180.3	P12109
	COL6A1	ENST00000866134.1		c.564+37C>A		intron	N/A	ENSP00000536193.1

Frequencies

GnomAD3 genomes AF: 0.701 AC: 106351 AN: 151606 Hom.: 38390 Cov.: 31

Gnomad AFR AF: 0.515

Gnomad AMI AF: 0.848

Gnomad AMR AF: 0.755

Gnomad ASJ AF: 0.762

Gnomad EAS AF: 0.779

Gnomad SAS AF: 0.723

Gnomad FIN AF: 0.842

Gnomad MID AF: 0.780

Gnomad NFE AF: 0.767

Gnomad OTH AF: 0.743

GnomAD2 exomes AF: 0.752 AC: 113636 AN: 151150 AF XY: 0.752

Gnomad AFR exome AF: 0.518

Gnomad AMR exome AF: 0.768

Gnomad ASJ exome AF: 0.753

Gnomad EAS exome AF: 0.787

Gnomad FIN exome AF: 0.840

Gnomad NFE exome AF: 0.766

Gnomad OTH exome AF: 0.772

GnomAD4 exome AF: 0.755 AC: 1050445 AN: 1391858 Hom.: 398163 Cov.: 57 AF XY: 0.755 AC XY: 518132 AN XY: 686646

African (AFR) AF: 0.499 AC: 15744 AN: 31564

American (AMR) AF: 0.770 AC: 27529 AN: 35740

Ashkenazi Jewish (ASJ) AF: 0.755 AC: 19010 AN: 25180

East Asian (EAS) AF: 0.754 AC: 26951 AN: 35732

South Asian (SAS) AF: 0.719 AC: 56977 AN: 79198

European-Finnish (FIN) AF: 0.836 AC: 35745 AN: 42772

Middle Eastern (MID) AF: 0.773 AC: 3925 AN: 5080

European-Non Finnish (NFE) AF: 0.761 AC: 820922 AN: 1078724

Other (OTH) AF: 0.754 AC: 43642 AN: 57868

GnomAD4 genome AF: 0.701 AC: 106415 AN: 151728 Hom.: 38410 Cov.: 31 AF XY: 0.705 AC XY: 52240 AN XY: 74148

African (AFR) AF: 0.515 AC: 21298 AN: 41352

American (AMR) AF: 0.755 AC: 11521 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.762 AC: 2644 AN: 3470

East Asian (EAS) AF: 0.780 AC: 3973 AN: 5096

South Asian (SAS) AF: 0.722 AC: 3466 AN: 4800

European-Finnish (FIN) AF: 0.842 AC: 8925 AN: 10594

Middle Eastern (MID) AF: 0.789 AC: 232 AN: 294

European-Non Finnish (NFE) AF: 0.767 AC: 52008 AN: 67834

Other (OTH) AF: 0.746 AC: 1576 AN: 2112

Alfa AF: 0.734 Hom.: 8385

Bravo AF: 0.689

Asia WGS AF: 0.775 AC: 2694 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Bethlem myopathy 1A (2)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	not provided (1)
-	-	1	Ullrich congenital muscular dystrophy 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.4
DANN	Benign	0.68
PhyloP100		0.15
Mutation Taster		=9/91	disease causing

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: rs754507; hg19: chr21-47406612; COSMIC: COSV62616090; COSMIC: COSV62616090;