chr21-45996410-C-T

Variant names:

• chr21-45996410-C-T
• rs9978314
• NM_001848.3:c.1399-1011C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001848.3(COL6A1):​c.1399-1011C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 152,112 control chromosomes in the GnomAD database, including 20,939 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.52 (20939 hom., cov: 33)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.10
• Publications: 16 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.608 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.1399-1011C>T		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.1399-1011C>T		intron	N/A	ENSP00000355180.3	P12109
	COL6A1	ENST00000866134.1		c.565-6117C>T		intron	N/A	ENSP00000536193.1
	COL6A1	ENST00000683550.1		n.174-1011C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78659 AN: 151994 Hom.: 20915 Cov.: 33

Gnomad AFR AF: 0.615

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.462

Gnomad ASJ AF: 0.419

Gnomad EAS AF: 0.235

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.485

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.515

Gnomad OTH AF: 0.483

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.518 AC: 78729 AN: 152112 Hom.: 20939 Cov.: 33 AF XY: 0.512 AC XY: 38049 AN XY: 74354

African (AFR) AF: 0.614 AC: 25505 AN: 41506

American (AMR) AF: 0.462 AC: 7068 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 1451 AN: 3466

East Asian (EAS) AF: 0.234 AC: 1209 AN: 5162

South Asian (SAS) AF: 0.388 AC: 1873 AN: 4826

European-Finnish (FIN) AF: 0.485 AC: 5131 AN: 10578

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.515 AC: 35008 AN: 67966

Other (OTH) AF: 0.478 AC: 1010 AN: 2112

Alfa AF: 0.496 Hom.: 21426

Bravo AF: 0.520

Asia WGS AF: 0.307 AC: 1071 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.92
DANN	Benign	0.63
PhyloP100		-2.1
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: rs9978314; hg19: chr21-47416324;