21-46120530-G-A

Variant names:

• chr21-46120530-G-A
• rs757846451
• NM_001849.4:c.1348G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001849.4(COL6A2):​c.1348G>A​(p.Glu450Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000149 in 1,339,492 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E450Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.92
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1348G>A	p.Glu450Lys	missense	Exon 16 of 28	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.1348G>A	p.Glu450Lys	missense	Exon 16 of 28	NP_478054.2
	COL6A2	NM_058175.3		c.1348G>A	p.Glu450Lys	missense	Exon 16 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.1348G>A	p.Glu450Lys	missense	Exon 16 of 28	ENSP00000300527.4
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.1348G>A	p.Glu450Lys	missense	Exon 16 of 28	ENSP00000380870.1
	COL6A2	ENST00000409416.6	TSL:5	c.1348G>A	p.Glu450Lys	missense	Exon 15 of 27	ENSP00000387115.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000149 AC: 2 AN: 1339492 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 657876

African (AFR) AF: 0.00 AC: 0 AN: 28638

American (AMR) AF: 0.00 AC: 0 AN: 23040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21140

East Asian (EAS) AF: 0.0000290 AC: 1 AN: 34538

South Asian (SAS) AF: 0.00 AC: 0 AN: 70530

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5086

European-Non Finnish (NFE) AF: 9.48e-7 AC: 1 AN: 1055322

Other (OTH) AF: 0.00 AC: 0 AN: 55096

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	-0.50	N
PhyloP100		3.9
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.57
Sift	Benign	0.17	T
Sift4G	Benign	0.58	T
Polyphen		0.99	D
Vest4		0.46
MutPred		0.49		Gain of glycosylation at E450 (P = 0.0019)
MVP		0.99
MPC		0.65
ClinPred		0.97	D
GERP RS		4.4
PromoterAI		-0.0052	Neutral
Varity_R		0.20
gMVP		0.58
Mutation Taster		=25/75	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs757846451; hg19: chr21-47540444;