rs74982956

Variant names:

• chr21-45991080-C-T
• rs74982956
• NM_001848.3:c.1119+39C>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.1119+39C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00903 in 1,606,404 control chromosomes in the GnomAD database, including 899 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0085 (76 hom., cov: 33)
  • Exomes 𝑓: 0.0091 (823 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.33
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 21-45991080-C-T is Benign according to our data. Variant chr21-45991080-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.138 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.1119+39C>T		intron	N/A	NP_001839.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	ENST00000361866.8	TSL:1 MANE Select	c.1119+39C>T		intron	N/A	ENSP00000355180.3
	COL6A1	ENST00000866134.1		c.564+4419C>T		intron	N/A	ENSP00000536193.1

Frequencies

GnomAD3 genomes AF: 0.00852 AC: 1297 AN: 152184 Hom.: 76 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.0429

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.0183 AC: 4525 AN: 247546 AF XY: 0.0185

Gnomad AFR exome AF: 0.000380

Gnomad AMR exome AF: 0.0115

Gnomad ASJ exome AF: 0.00542

Gnomad EAS exome AF: 0.139

Gnomad FIN exome AF: 0.00269

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.00909 AC: 13215 AN: 1454102 Hom.: 823 Cov.: 32 AF XY: 0.00991 AC XY: 7174 AN XY: 723736

African (AFR) AF: 0.000511 AC: 17 AN: 33286

American (AMR) AF: 0.0116 AC: 520 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00606 AC: 158 AN: 26090

East Asian (EAS) AF: 0.182 AC: 7208 AN: 39660

South Asian (SAS) AF: 0.0423 AC: 3646 AN: 86130

European-Finnish (FIN) AF: 0.00279 AC: 146 AN: 52318

Middle Eastern (MID) AF: 0.0104 AC: 60 AN: 5754

European-Non Finnish (NFE) AF: 0.000702 AC: 777 AN: 1106056

Other (OTH) AF: 0.0114 AC: 683 AN: 60160

GnomAD4 genome AF: 0.00850 AC: 1295 AN: 152302 Hom.: 76 Cov.: 33 AF XY: 0.0103 AC XY: 770 AN XY: 74468

African (AFR) AF: 0.000505 AC: 21 AN: 41562

American (AMR) AF: 0.0129 AC: 198 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.146 AC: 756 AN: 5162

South Asian (SAS) AF: 0.0427 AC: 206 AN: 4822

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000735 AC: 50 AN: 68036

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00315 Hom.: 2

Bravo AF: 0.00905

Asia WGS AF: 0.0690 AC: 238 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)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.9
DANN	Benign	0.68
PhyloP100		-3.3
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: rs74982956; hg19: chr21-47410994; COSMIC: COSV62612161; COSMIC: COSV62612161;