21-45989325-G-C

Variant names:

• chr21-45989325-G-C
• rs2277813
• NM_001848.3:c.858+188G>C

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.858+188G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.684 in 152,194 control chromosomes in the GnomAD database, including 35,859 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.68 (35859 hom., cov: 35)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.931
• Publications: 8 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=-0.94).
• BP6: Variant 21-45989325-G-C is Benign according to our data. Variant chr21-45989325-G-C is described in CliVar as Benign. Clinvar id is 679178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45989325-G-C is described in CliVar as Benign. Clinvar id is 679178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45989325-G-C is described in CliVar as Benign. Clinvar id is 679178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.779 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A1	NM_001848.3	c.858+188G>C		intron_variant	Intron 9 of 34	ENST00000361866.8	NP_001839.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8	c.858+188G>C		intron_variant	Intron 9 of 34	1	NM_001848.3	ENSP00000355180.3

Frequencies

GnomAD3 genomes AF: 0.684 AC: 104069 AN: 152076 Hom.: 35820 Cov.: 35

Gnomad AFR AF: 0.729

Gnomad AMI AF: 0.554

Gnomad AMR AF: 0.720

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.799

Gnomad SAS AF: 0.609

Gnomad FIN AF: 0.703

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.651

Gnomad OTH AF: 0.680

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

GnomAD4 genome AF: 0.684 AC: 104163 AN: 152194 Hom.: 35859 Cov.: 35 AF XY: 0.683 AC XY: 50827 AN XY: 74410

African (AFR) AF: 0.729 AC: 30268 AN: 41542

American (AMR) AF: 0.720 AC: 11018 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 1973 AN: 3470

East Asian (EAS) AF: 0.799 AC: 4133 AN: 5170

South Asian (SAS) AF: 0.610 AC: 2942 AN: 4824

European-Finnish (FIN) AF: 0.703 AC: 7457 AN: 10604

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.651 AC: 44251 AN: 67960

Other (OTH) AF: 0.681 AC: 1440 AN: 2116

Alfa AF: 0.590 Hom.: 1904

Bravo AF: 0.690

Asia WGS AF: 0.701 AC: 2438 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.79
DANN	Benign	0.63
PhyloP100		-0.93
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: rs2277813; hg19: chr21-47409239;