21-45986676-C-T

Variant names:

• chr21-45986676-C-T
• rs61751027
• NM_001848.3:c.579C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001848.3(COL6A1):​c.579C>T​(p.Pro193Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000893 in 1,547,322 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (7 hom.)
• Consequence: COL6A1 NM_001848.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.21
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 21-45986676-C-T is Benign according to our data. Variant chr21-45986676-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.21 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00474 (717/151242) while in subpopulation AFR AF = 0.0165 (675/40944). AF 95% confidence interval is 0.0155. There are 7 homozygotes in GnomAd4. There are 321 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	NM_001848.3	MANE Select	c.579C>T	p.Pro193Pro	synonymous	Exon 4 of 35	NP_001839.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	ENST00000361866.8	TSL:1 MANE Select	c.579C>T	p.Pro193Pro	synonymous	Exon 4 of 35	ENSP00000355180.3
	COL6A1	ENST00000866134.1		c.564+15C>T		intron	N/A	ENSP00000536193.1

Frequencies

GnomAD3 genomes AF: 0.00477 AC: 721 AN: 151124 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00111 AC: 172 AN: 154360 AF XY: 0.000736

Gnomad AFR exome AF: 0.0160

Gnomad AMR exome AF: 0.000887

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000827

Gnomad OTH exome AF: 0.000911

GnomAD4 exome AF: 0.000476 AC: 664 AN: 1396080 Hom.: 7 Cov.: 33 AF XY: 0.000393 AC XY: 271 AN XY: 688742

African (AFR) AF: 0.0158 AC: 499 AN: 31604

American (AMR) AF: 0.000921 AC: 33 AN: 35842

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25188

East Asian (EAS) AF: 0.00 AC: 0 AN: 35746

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45962

Middle Eastern (MID) AF: 0.00199 AC: 11 AN: 5520

European-Non Finnish (NFE) AF: 0.0000482 AC: 52 AN: 1079046

Other (OTH) AF: 0.00117 AC: 68 AN: 57942

GnomAD4 genome AF: 0.00474 AC: 717 AN: 151242 Hom.: 7 Cov.: 32 AF XY: 0.00434 AC XY: 321 AN XY: 73904

African (AFR) AF: 0.0165 AC: 675 AN: 40944

American (AMR) AF: 0.00177 AC: 27 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5074

South Asian (SAS) AF: 0.00 AC: 0 AN: 4768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67842

Other (OTH) AF: 0.00332 AC: 7 AN: 2108

Alfa AF: 0.00218 Hom.: 2

Bravo AF: 0.00560

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.061
DANN	Benign	0.51
PhyloP100		-1.2
Mutation Taster		=99/1	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: rs61751027; hg19: chr21-47406590;