rs2075893

Variant names:

• chr21-45992926-C-T
• rs2075893
• NM_001848.3:c.1335+116C>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.1335+116C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 928,246 control chromosomes in the GnomAD database, including 58,474 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8350 hom., cov: 34)
  • Exomes 𝑓: 0.35 (50124 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.433
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 21-45992926-C-T is Benign according to our data. Variant chr21-45992926-C-T is described in ClinVar as Benign. ClinVar VariationId is 679937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A1	NM_001848.3	c.1335+116C>T		intron_variant	Intron 19 of 34	ENST00000361866.8	NP_001839.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8	c.1335+116C>T		intron_variant	Intron 19 of 34	1	NM_001848.3	ENSP00000355180.3

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46826 AN: 151974 Hom.: 8344 Cov.: 34

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.370

Gnomad EAS AF: 0.633

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.386

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.333

GnomAD4 exome AF: 0.351 AC: 272400 AN: 776154 Hom.: 50124 AF XY: 0.353 AC XY: 139819 AN XY: 396366

African (AFR) AF: 0.147 AC: 2748 AN: 18702

American (AMR) AF: 0.496 AC: 14281 AN: 28798

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 6830 AN: 18542

East Asian (EAS) AF: 0.615 AC: 19657 AN: 31982

South Asian (SAS) AF: 0.380 AC: 22990 AN: 60490

European-Finnish (FIN) AF: 0.391 AC: 17800 AN: 45554

Middle Eastern (MID) AF: 0.369 AC: 1050 AN: 2844

European-Non Finnish (NFE) AF: 0.327 AC: 174262 AN: 532870

Other (OTH) AF: 0.351 AC: 12782 AN: 36372

GnomAD4 genome AF: 0.308 AC: 46837 AN: 152092 Hom.: 8350 Cov.: 34 AF XY: 0.314 AC XY: 23305 AN XY: 74336

African (AFR) AF: 0.151 AC: 6271 AN: 41548

American (AMR) AF: 0.418 AC: 6396 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 1284 AN: 3472

East Asian (EAS) AF: 0.633 AC: 3251 AN: 5132

South Asian (SAS) AF: 0.397 AC: 1916 AN: 4824

European-Finnish (FIN) AF: 0.386 AC: 4090 AN: 10584

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.330 AC: 22436 AN: 67932

Other (OTH) AF: 0.337 AC: 712 AN: 2110

Alfa AF: 0.314 Hom.: 1811

Bravo AF: 0.305

Asia WGS AF: 0.503 AC: 1746 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.1
DANN	Benign	0.55
PhyloP100		-0.43
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: rs2075893; hg19: chr21-47412840; COSMIC: COSV62611344;