21-45997664-A-G

Variant names:

• chr21-45997664-A-G
• rs2276255
• NM_001848.3:c.1462-36A>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.1462-36A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 1,569,028 control chromosomes in the GnomAD database, including 77,947 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.34 (9489 hom., cov: 34)
  • Exomes 𝑓: 0.31 (68458 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.31
• Publications: 11 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 21-45997664-A-G is Benign according to our data. Variant chr21-45997664-A-G is described in ClinVar as Benign. ClinVar VariationId is 93817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.46 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	NM_001848.3	MANE Select	c.1462-36A>G		intron	N/A	NP_001839.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	ENST00000361866.8	TSL:1 MANE Select	c.1462-36A>G		intron	N/A	ENSP00000355180.3
	COL6A1	ENST00000683550.1		n.237-36A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.342 AC: 51891 AN: 151834 Hom.: 9476 Cov.: 34

Gnomad AFR AF: 0.465

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.309

Gnomad OTH AF: 0.318

GnomAD2 exomes AF: 0.288 AC: 52130 AN: 181320 AF XY: 0.281

Gnomad AFR exome AF: 0.462

Gnomad AMR exome AF: 0.304

Gnomad ASJ exome AF: 0.234

Gnomad EAS exome AF: 0.151

Gnomad FIN exome AF: 0.280

Gnomad NFE exome AF: 0.309

Gnomad OTH exome AF: 0.277

GnomAD4 exome AF: 0.307 AC: 435528 AN: 1417076 Hom.: 68458 Cov.: 35 AF XY: 0.304 AC XY: 212915 AN XY: 701030

African (AFR) AF: 0.473 AC: 15313 AN: 32354

American (AMR) AF: 0.302 AC: 11571 AN: 38264

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 5979 AN: 25370

East Asian (EAS) AF: 0.196 AC: 7284 AN: 37166

South Asian (SAS) AF: 0.232 AC: 18800 AN: 81024

European-Finnish (FIN) AF: 0.278 AC: 13770 AN: 49474

Middle Eastern (MID) AF: 0.254 AC: 1443 AN: 5692

European-Non Finnish (NFE) AF: 0.316 AC: 344250 AN: 1088946

Other (OTH) AF: 0.291 AC: 17118 AN: 58786

GnomAD4 genome AF: 0.342 AC: 51947 AN: 151952 Hom.: 9489 Cov.: 34 AF XY: 0.340 AC XY: 25280 AN XY: 74288

African (AFR) AF: 0.465 AC: 19294 AN: 41456

American (AMR) AF: 0.332 AC: 5078 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 808 AN: 3472

East Asian (EAS) AF: 0.166 AC: 852 AN: 5126

South Asian (SAS) AF: 0.221 AC: 1065 AN: 4820

European-Finnish (FIN) AF: 0.285 AC: 3013 AN: 10588

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.309 AC: 20944 AN: 67888

Other (OTH) AF: 0.314 AC: 663 AN: 2112

Alfa AF: 0.311 Hom.: 1433

Bravo AF: 0.352

Asia WGS AF: 0.187 AC: 653 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 24, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Bethlem myopathy 1A Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ullrich congenital muscular dystrophy 1A Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.76
DANN	Benign	0.26
PhyloP100		-4.3
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2276255; hg19: chr21-47417578; COSMIC: COSV62612848; COSMIC: COSV62612848;