rs863224861

Variant names:

• chr21-46125911-G-A
• rs863224861
• NM_001849.4:c.2096G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_001849.4(COL6A2):​c.2096G>A​(p.Gly699Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G699G) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.76
• Publications: 2 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_001849.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 21-46125911-G-A is Pathogenic according to our data. Variant chr21-46125911-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 216911.

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.2096G>A	p.Gly699Asp	missense	Exon 26 of 28	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.2096G>A	p.Gly699Asp	missense	Exon 26 of 28	NP_478054.2	P12110-2
	COL6A2	NM_058175.3		c.2096G>A	p.Gly699Asp	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.2096G>A	p.Gly699Asp	missense	Exon 26 of 28	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.2096G>A	p.Gly699Asp	missense	Exon 26 of 28	ENSP00000380870.1	P12110-2
	COL6A2	ENST00000857098.1		c.2291G>A	p.Gly764Asp	missense	Exon 26 of 28	ENSP00000527157.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 73

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Bethlem myopathy 1A (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		9.8
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.057	T
Polyphen		1.0	D
Vest4		0.89
MutPred		0.81		Loss of catalytic residue at A698 (P = 0.0507)
MVP		0.95
MPC		0.70
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.83
gMVP		0.97
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs863224861; hg19: chr21-47545825;