rs1042917

Variant names:

• chr21-46125854-G-A
• rs1042917
• NM_001849.4:c.2039G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-46125854-G-A
• chr21-46125854-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001849.4(COL6A2):​c.2039G>A​(p.Arg680His) variant causes a missense change. The variant allele was found at a frequency of 0.483 in 1,612,622 control chromosomes in the GnomAD database, including 194,042 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R680C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.45 (16357 hom., cov: 32)
  • Exomes 𝑓: 0.49 (177685 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 4.95
• Publications: 54 publications found

Genes affected

COL6A2 (HGNC:2212): (collagen type VI alpha 2 chain) This gene encodes one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The product of this gene contains several domains similar to von Willebrand Factor type A domains. These domains have been shown to bind extracellular matrix proteins, an interaction that explains the importance of this collagen in organizing matrix components. Mutations in this gene are associated with Bethlem myopathy and Ullrich scleroatonic muscular dystrophy. Three transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]

COL6A2 Gene-Disease associations (from GenCC):

• collagen 6-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1B

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: G2P
• Bethlem myopathy 1A

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
• 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
• myosclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.4074334E-5).
• BP6: Variant 21-46125854-G-A is Benign according to our data. Variant chr21-46125854-G-A is described in ClinVar as Benign. ClinVar VariationId is 93929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.567 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001849.4. 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
	COL6A2	NM_001849.4	MANE Select	c.2039G>A	p.Arg680His	missense	Exon 26 of 28	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.2039G>A	p.Arg680His	missense	Exon 26 of 28	NP_478054.2
	COL6A2	NM_058175.3		c.2039G>A	p.Arg680His	missense	Exon 26 of 28	NP_478055.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	ENST00000300527.9	TSL:1 MANE Select	c.2039G>A	p.Arg680His	missense	Exon 26 of 28	ENSP00000300527.4
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.2039G>A	p.Arg680His	missense	Exon 26 of 28	ENSP00000380870.1
	COL6A2	ENST00000409416.6	TSL:5	c.2039G>A	p.Arg680His	missense	Exon 25 of 27	ENSP00000387115.1

Frequencies

GnomAD3 genomes AF: 0.445 AC: 67577 AN: 151798 Hom.: 16342 Cov.: 32

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.582

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.524

Gnomad EAS AF: 0.449

Gnomad SAS AF: 0.333

Gnomad FIN AF: 0.617

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.509

Gnomad OTH AF: 0.460

GnomAD2 exomes AF: 0.492 AC: 123178 AN: 250564 AF XY: 0.482

Gnomad AFR exome AF: 0.241

Gnomad AMR exome AF: 0.653

Gnomad ASJ exome AF: 0.520

Gnomad EAS exome AF: 0.440

Gnomad FIN exome AF: 0.623

Gnomad NFE exome AF: 0.502

Gnomad OTH exome AF: 0.517

GnomAD4 exome AF: 0.487 AC: 711956 AN: 1460706 Hom.: 177685 Cov.: 72 AF XY: 0.483 AC XY: 350764 AN XY: 726668

African (AFR) AF: 0.229 AC: 7675 AN: 33480

American (AMR) AF: 0.644 AC: 28799 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 13607 AN: 26132

East Asian (EAS) AF: 0.433 AC: 17172 AN: 39694

South Asian (SAS) AF: 0.331 AC: 28561 AN: 86256

European-Finnish (FIN) AF: 0.614 AC: 32193 AN: 52398

Middle Eastern (MID) AF: 0.431 AC: 2486 AN: 5768

European-Non Finnish (NFE) AF: 0.497 AC: 552640 AN: 1111894

Other (OTH) AF: 0.477 AC: 28823 AN: 60380

GnomAD4 genome AF: 0.445 AC: 67612 AN: 151916 Hom.: 16357 Cov.: 32 AF XY: 0.451 AC XY: 33455 AN XY: 74220

African (AFR) AF: 0.250 AC: 10381 AN: 41448

American (AMR) AF: 0.577 AC: 8807 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.524 AC: 1818 AN: 3470

East Asian (EAS) AF: 0.450 AC: 2299 AN: 5110

South Asian (SAS) AF: 0.333 AC: 1601 AN: 4814

European-Finnish (FIN) AF: 0.617 AC: 6519 AN: 10564

Middle Eastern (MID) AF: 0.432 AC: 126 AN: 292

European-Non Finnish (NFE) AF: 0.509 AC: 34571 AN: 67928

Other (OTH) AF: 0.455 AC: 959 AN: 2106

Alfa AF: 0.477 Hom.: 78432

Bravo AF: 0.436

TwinsUK AF: 0.499 AC: 1851

ALSPAC AF: 0.516 AC: 1987

ESP6500AA AF: 0.241 AC: 1061

ESP6500EA AF: 0.501 AC: 4310

ExAC AF: 0.477 AC: 57872

Asia WGS AF: 0.402 AC: 1396 AN: 3478

EpiCase AF: 0.492

EpiControl AF: 0.489

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Bethlem myopathy 1A (3)
-	-	3	not provided (3)
-	-	2	Myosclerosis (2)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	Ullrich congenital muscular dystrophy 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.000094	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.5	L
PhyloP100		5.0
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.28
Sift	Benign	0.081	T
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.43
MPC		0.68
ClinPred		0.011	T
GERP RS		4.4
Varity_R		0.22
gMVP		0.72
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1042917; hg19: chr21-47545768; COSMIC: COSV56000676;