21-45994974-A-C

Variant names:

• chr21-45994974-A-C
• rs2850175
• NM_001848.3:c.1398+745A>C

Variant summary

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

The NM_001848.3(COL6A1):​c.1398+745A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.878 in 152,328 control chromosomes in the GnomAD database, including 58,828 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 0.88 (58828 hom., cov: 35)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.17
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.912 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A1	NM_001848.3	c.1398+745A>C		intron_variant	Intron 20 of 34	ENST00000361866.8	NP_001839.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8	c.1398+745A>C		intron_variant	Intron 20 of 34	1	NM_001848.3	ENSP00000355180.3
COL6A1	ENST00000683550.1	n.173+745A>C		intron_variant	Intron 1 of 4

Frequencies

GnomAD3 genomes AF: 0.878 AC: 133629 AN: 152210 Hom.: 58765 Cov.: 35

Gnomad AFR AF: 0.920

Gnomad AMI AF: 0.827

Gnomad AMR AF: 0.905

Gnomad ASJ AF: 0.802

Gnomad EAS AF: 0.869

Gnomad SAS AF: 0.780

Gnomad FIN AF: 0.886

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.859

Gnomad OTH AF: 0.850

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

GnomAD4 genome AF: 0.878 AC: 133748 AN: 152328 Hom.: 58828 Cov.: 35 AF XY: 0.877 AC XY: 65331 AN XY: 74480

African (AFR) AF: 0.920 AC: 38242 AN: 41582

American (AMR) AF: 0.905 AC: 13858 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.802 AC: 2783 AN: 3472

East Asian (EAS) AF: 0.869 AC: 4492 AN: 5170

South Asian (SAS) AF: 0.781 AC: 3772 AN: 4830

European-Finnish (FIN) AF: 0.886 AC: 9408 AN: 10618

Middle Eastern (MID) AF: 0.755 AC: 222 AN: 294

European-Non Finnish (NFE) AF: 0.859 AC: 58421 AN: 68024

Other (OTH) AF: 0.849 AC: 1796 AN: 2116

Alfa AF: 0.861 Hom.: 2768

Bravo AF: 0.883

Asia WGS AF: 0.815 AC: 2836 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.013
DANN	Benign	0.42
PhyloP100		-3.2
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: rs2850175; hg19: chr21-47414888;