21-45981846-C-G

Variant names:

• chr21-45981846-C-G
• rs7671
• NM_001848.3:c.-5C>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.-5C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 1,574,586 control chromosomes in the GnomAD database, including 216,813 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18376 hom., cov: 24)
  • Exomes 𝑓: 0.52 (198437 hom.)
• Consequence: COL6A1 NM_001848.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.257
• Publications: 15 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, AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AR, AD 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=-0.9).
• BP6: Variant 21-45981846-C-G is Benign according to our data. Variant chr21-45981846-C-G is described in ClinVar as Benign. ClinVar VariationId is 93792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.75 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.-5C>G		5_prime_UTR	Exon 1 of 35	NP_001839.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	ENST00000361866.8	TSL:1 MANE Select	c.-5C>G		5_prime_UTR	Exon 1 of 35	ENSP00000355180.3
	COL6A1	ENST00000866134.1		c.-5C>G		5_prime_UTR	Exon 1 of 7	ENSP00000536193.1

Frequencies

GnomAD3 genomes AF: 0.477 AC: 71156 AN: 149192 Hom.: 18365 Cov.: 24

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.605

Gnomad AMR AF: 0.556

Gnomad ASJ AF: 0.583

Gnomad EAS AF: 0.770

Gnomad SAS AF: 0.621

Gnomad FIN AF: 0.562

Gnomad MID AF: 0.660

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.539

GnomAD2 exomes AF: 0.555 AC: 104340 AN: 188092 AF XY: 0.557

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.604

Gnomad ASJ exome AF: 0.573

Gnomad EAS exome AF: 0.774

Gnomad FIN exome AF: 0.557

Gnomad NFE exome AF: 0.516

Gnomad OTH exome AF: 0.576

GnomAD4 exome AF: 0.523 AC: 744998 AN: 1425282 Hom.: 198437 Cov.: 34 AF XY: 0.527 AC XY: 372074 AN XY: 706378

African (AFR) AF: 0.272 AC: 8843 AN: 32534

American (AMR) AF: 0.604 AC: 24454 AN: 40506

Ashkenazi Jewish (ASJ) AF: 0.580 AC: 14811 AN: 25526

East Asian (EAS) AF: 0.748 AC: 27963 AN: 37406

South Asian (SAS) AF: 0.606 AC: 49465 AN: 81590

European-Finnish (FIN) AF: 0.563 AC: 27755 AN: 49316

Middle Eastern (MID) AF: 0.611 AC: 2678 AN: 4386

European-Non Finnish (NFE) AF: 0.509 AC: 557304 AN: 1095124

Other (OTH) AF: 0.539 AC: 31725 AN: 58894

GnomAD4 genome AF: 0.477 AC: 71194 AN: 149304 Hom.: 18376 Cov.: 24 AF XY: 0.482 AC XY: 35079 AN XY: 72772

African (AFR) AF: 0.284 AC: 11522 AN: 40562

American (AMR) AF: 0.555 AC: 8361 AN: 15054

Ashkenazi Jewish (ASJ) AF: 0.583 AC: 2013 AN: 3452

East Asian (EAS) AF: 0.770 AC: 3768 AN: 4892

South Asian (SAS) AF: 0.619 AC: 2865 AN: 4630

European-Finnish (FIN) AF: 0.562 AC: 5779 AN: 10286

Middle Eastern (MID) AF: 0.662 AC: 192 AN: 290

European-Non Finnish (NFE) AF: 0.521 AC: 35021 AN: 67164

Other (OTH) AF: 0.544 AC: 1132 AN: 2080

Alfa AF: 0.490 Hom.: 5441

Bravo AF: 0.470

Asia WGS AF: 0.703 AC: 2443 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	8.7
DANN	Benign	0.48
PhyloP100		0.26
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=298/2	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: rs7671; hg19: chr21-47401760;