NM_001849.4:c.2893C>T

Variant names:

• chr21-46132385-C-T
• rs201188174
• NM_001849.4:c.2893C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3 BP6

The NM_001849.4(COL6A2):​c.2893C>T​(p.Arg965Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000388 in 1,609,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R965H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 2.45
• 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, 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: Uncertain_significance. The variant received 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.77
• BP6: Variant 21-46132385-C-T is Benign according to our data. Variant chr21-46132385-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 283255.

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.2893C>T	p.Arg965Cys	missense	Exon 28 of 28	NP_001840.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	ENST00000300527.9	TSL:1 MANE Select	c.2893C>T	p.Arg965Cys	missense	Exon 28 of 28	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000857098.1		c.3088C>T	p.Arg1030Cys	missense	Exon 28 of 28	ENSP00000527157.1
	COL6A2	ENST00000857103.1		c.3055C>T	p.Arg1019Cys	missense	Exon 28 of 28	ENSP00000527162.1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152236 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000175 AC: 43 AN: 245502 AF XY: 0.000164

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000550

Gnomad FIN exome AF: 0.000314

Gnomad NFE exome AF: 0.000288

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000405 AC: 590 AN: 1457132 Hom.: 0 Cov.: 35 AF XY: 0.000383 AC XY: 278 AN XY: 724976

African (AFR) AF: 0.000120 AC: 4 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39656

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86248

European-Finnish (FIN) AF: 0.000464 AC: 23 AN: 49604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000459 AC: 510 AN: 1111294

Other (OTH) AF: 0.000746 AC: 45 AN: 60304

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152354 Hom.: 0 Cov.: 34 AF XY: 0.000282 AC XY: 21 AN XY: 74504

African (AFR) AF: 0.000168 AC: 7 AN: 41584

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000376 AC: 4 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000358 Hom.: 0

Bravo AF: 0.000223

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000491

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	-	1	Bethlem myopathy 1A (1)
-	-	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	Pathogenic	0.75
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.58
MVP		0.97
MPC		0.69
ClinPred		0.46	T
GERP RS		3.4
Varity_R		0.37
gMVP		0.86
Mutation Taster		=37/63	disease causing

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: rs201188174; hg19: chr21-47552299; COSMIC: COSV52424523; COSMIC: COSV52424523;