21-46122529-G-A

Variant names:

• chr21-46122529-G-A
• rs143338050
• NM_001849.4:c.1606G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001849.4(COL6A2):​c.1606G>A​(p.Glu536Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,612,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: COL6A2 NM_001849.4 missense, splice_region
• Scores: Splicing: ADA: 0.0003318
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 1.39
• Publications: 3 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_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06379464).
• BP6: Variant 21-46122529-G-A is Benign according to our data. Variant chr21-46122529-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 476454.

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.1606G>A	p.Glu536Lys	missense splice_region	Exon 20 of 28	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.1606G>A	p.Glu536Lys	missense splice_region	Exon 20 of 28	NP_478054.2	P12110-2
	COL6A2	NM_058175.3		c.1606G>A	p.Glu536Lys	missense splice_region	Exon 20 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.1606G>A	p.Glu536Lys	missense splice_region	Exon 20 of 28	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.1606G>A	p.Glu536Lys	missense splice_region	Exon 20 of 28	ENSP00000380870.1	P12110-2
	COL6A2	ENST00000857098.1		c.1801G>A	p.Glu601Lys	missense splice_region	Exon 20 of 28	ENSP00000527157.1

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152056 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000173 AC: 43 AN: 249096 AF XY: 0.000148

Gnomad AFR exome AF: 0.0000626

Gnomad AMR exome AF: 0.000782

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000893

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000135 AC: 197 AN: 1460474 Hom.: 0 Cov.: 34 AF XY: 0.000111 AC XY: 81 AN XY: 726524

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.000738 AC: 33 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86254

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000130 AC: 145 AN: 1111950

Other (OTH) AF: 0.000215 AC: 13 AN: 60364

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74384

African (AFR) AF: 0.000120 AC: 5 AN: 41544

American (AMR) AF: 0.000131 AC: 2 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000234 Hom.: 0

Bravo AF: 0.000128

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000173 AC: 21

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Collagen 6-related myopathy (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	-0.81	N
PhyloP100		1.4
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.060	N
REVEL	Uncertain	0.41
Sift	Benign	0.61	T
Sift4G	Benign	0.86	T
Polyphen		0.095	B
Vest4		0.35
MVP		0.96
MPC		0.16
ClinPred		0.045	T
GERP RS		4.3
Varity_R		0.074
gMVP		0.25
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00033
dbscSNV1_RF	Benign	0.016
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: rs143338050; hg19: chr21-47542443; COSMIC: COSV56016652;