NM_001849.4:c.2351G>A

Variant names:

• chr21-46126166-G-A
• rs75120695
• NM_001849.4:c.2351G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001849.4(COL6A2):​c.2351G>A​(p.Arg784His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00581 in 1,608,916 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R784P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0042 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0060 (33 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.40
• Publications: 14 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, SD, 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: AR, AD 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
• 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=0.011590838).
• BP6: Variant 21-46126166-G-A is Benign according to our data. Variant chr21-46126166-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00597 (8703/1456590) while in subpopulation NFE AF = 0.00716 (7964/1111958). AF 95% confidence interval is 0.00703. There are 33 homozygotes in GnomAdExome4. There are 4242 alleles in the male GnomAdExome4 subpopulation. Median coverage is 38. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR,SD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	NM_001849.4	MANE Select	c.2351G>A	p.Arg784His	missense	Exon 26 of 28	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.2351G>A	p.Arg784His	missense	Exon 26 of 28	NP_478054.2	P12110-2
	COL6A2	NM_058175.3		c.2351G>A	p.Arg784His	missense	Exon 26 of 28	NP_478055.2	P12110-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	ENST00000300527.9	TSL:1 MANE Select	c.2351G>A	p.Arg784His	missense	Exon 26 of 28	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.2351G>A	p.Arg784His	missense	Exon 26 of 28	ENSP00000380870.1	P12110-2
	COL6A2	ENST00000857098.1		c.2546G>A	p.Arg849His	missense	Exon 26 of 28	ENSP00000527157.1

Frequencies

GnomAD3 genomes AF: 0.00421 AC: 641 AN: 152208 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00687

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00625

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00444 AC: 1096 AN: 246884 AF XY: 0.00441

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.00463

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00256

Gnomad NFE exome AF: 0.00704

Gnomad OTH exome AF: 0.00492

GnomAD4 exome AF: 0.00597 AC: 8703 AN: 1456590 Hom.: 33 Cov.: 38 AF XY: 0.00585 AC XY: 4242 AN XY: 724792

African (AFR) AF: 0.000717 AC: 24 AN: 33478

American (AMR) AF: 0.00445 AC: 199 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00149 AC: 39 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00105 AC: 91 AN: 86258

European-Finnish (FIN) AF: 0.00230 AC: 111 AN: 48244

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00716 AC: 7964 AN: 1111958

Other (OTH) AF: 0.00447 AC: 270 AN: 60338

GnomAD4 genome AF: 0.00421 AC: 642 AN: 152326 Hom.: 2 Cov.: 33 AF XY: 0.00381 AC XY: 284 AN XY: 74480

African (AFR) AF: 0.00144 AC: 60 AN: 41574

American (AMR) AF: 0.00686 AC: 105 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00626 AC: 426 AN: 68038

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00559 Hom.: 6

Bravo AF: 0.00426

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00616 AC: 53

ExAC AF: 0.00451 AC: 548

Asia WGS AF: 0.000867 AC: 3 AN: 3476

EpiCase AF: 0.00616

EpiControl AF: 0.00765

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	5	not specified (5)
-	-	2	Bethlem myopathy 1A (2)
-	-	1	Collagen 6-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Benign	0.93
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.46	N
PhyloP100		1.4
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.42
Sift	Benign	0.35	T
Sift4G	Benign	0.57	T
Polyphen		0.049	B
Vest4		0.48
MVP		0.70
MPC		0.17
ClinPred		0.012	T
GERP RS		2.8
Varity_R		0.081
gMVP		0.60
Mutation Taster		=91/9	polymorphism

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: rs75120695; hg19: chr21-47546080; COSMIC: COSV99039006; COSMIC: COSV99039006;