21-46132118-C-G

Variant names:

• chr21-46132118-C-G
• rs387906608
• NM_001849.4:c.2626C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_001849.4(COL6A2):​c.2626C>G​(p.Arg876Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000699 in 1,431,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R876S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.75
• Publications: 7 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 8 uncertain in NM_001849.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-46132118-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 29641.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99

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.2626C>G	p.Arg876Gly	missense	Exon 28 of 28	NP_001840.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	ENST00000300527.9	TSL:1 MANE Select	c.2626C>G	p.Arg876Gly	missense	Exon 28 of 28	ENSP00000300527.4
	COL6A2	ENST00000857098.1		c.2821C>G	p.Arg941Gly	missense	Exon 28 of 28	ENSP00000527157.1
	COL6A2	ENST00000857103.1		c.2788C>G	p.Arg930Gly	missense	Exon 28 of 28	ENSP00000527162.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000520 AC: 1 AN: 192306 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000346

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1431030 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 710210

African (AFR) AF: 0.00 AC: 0 AN: 32636

American (AMR) AF: 0.0000248 AC: 1 AN: 40278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25618

East Asian (EAS) AF: 0.00 AC: 0 AN: 37512

South Asian (SAS) AF: 0.00 AC: 0 AN: 82996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099426

Other (OTH) AF: 0.00 AC: 0 AN: 59296

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.8
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.84		Loss of stability (P = 0.0102)
MVP		0.92
MPC		0.69
ClinPred		0.94	D
GERP RS		4.2
Varity_R		0.73
gMVP		0.92
Mutation Taster		=20/80	disease causing

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: rs387906608; hg19: chr21-47552032;