chr21-46132050-G-A

Variant names:

• chr21-46132050-G-A
• rs144830948
• NM_001849.4:c.2558G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001849.4(COL6A2):​c.2558G>A​(p.Arg853Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,607,222 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R853W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0025 (20 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.861
• Publications: 8 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066322386).
• BP6: Variant 21-46132050-G-A is Benign according to our data. Variant chr21-46132050-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 162538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00173 (263/152274) while in subpopulation SAS AF = 0.00932 (45/4830). AF 95% confidence interval is 0.00716. There are 1 homozygotes in GnomAd4. There are 130 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 20 AR,AD gene

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.2558G>A	p.Arg853Gln	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.2558G>A	p.Arg853Gln	missense	Exon 28 of 28	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000857098.1		c.2753G>A	p.Arg918Gln	missense	Exon 28 of 28	ENSP00000527157.1
	COL6A2	ENST00000857103.1		c.2720G>A	p.Arg907Gln	missense	Exon 28 of 28	ENSP00000527162.1

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 265 AN: 152156 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00972

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00203

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00250 AC: 588 AN: 235058 AF XY: 0.00279

Gnomad AFR exome AF: 0.00115

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000592

Gnomad NFE exome AF: 0.00191

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00248 AC: 3615 AN: 1454948 Hom.: 20 Cov.: 33 AF XY: 0.00272 AC XY: 1969 AN XY: 724084

African (AFR) AF: 0.000898 AC: 30 AN: 33416

American (AMR) AF: 0.00173 AC: 77 AN: 44536

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26060

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39550

South Asian (SAS) AF: 0.00929 AC: 799 AN: 86044

European-Finnish (FIN) AF: 0.000185 AC: 9 AN: 48558

Middle Eastern (MID) AF: 0.00417 AC: 24 AN: 5760

European-Non Finnish (NFE) AF: 0.00224 AC: 2485 AN: 1110920

Other (OTH) AF: 0.00314 AC: 189 AN: 60104

GnomAD4 genome AF: 0.00173 AC: 263 AN: 152274 Hom.: 1 Cov.: 34 AF XY: 0.00175 AC XY: 130 AN XY: 74448

African (AFR) AF: 0.00137 AC: 57 AN: 41554

American (AMR) AF: 0.000981 AC: 15 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00932 AC: 45 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00203 AC: 138 AN: 68014

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00105 Hom.: 1

Bravo AF: 0.00153

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00268 AC: 23

ExAC AF: 0.00249 AC: 300

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Bethlem myopathy 1A (3)
-	-	3	not provided (3)
-	-	1	COL6A2-related disorder (1)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	Myosclerosis (1)
-	-	1	not specified (1)
-	-	1	Ullrich congenital muscular dystrophy 1A;C1850671:Myosclerosis;CN029274:Bethlem myopathy 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.49	N
PhyloP100		0.86
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.80	N
REVEL	Uncertain	0.46
Sift	Benign	0.12	T
Sift4G	Benign	0.13	T
Polyphen		0.15	B
Vest4		0.24
MVP		0.73
MPC		0.16
ClinPred		0.014	T
GERP RS		1.9
Varity_R		0.052
gMVP		0.53
Mutation Taster		=95/5	polymorphism

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: rs144830948; hg19: chr21-47551964;