rs61735828

Variant names:

• chr21-46121563-G-A
• rs61735828
• NM_001849.4:c.1466G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-46121563-G-A
• chr21-46121563-G-C
• chr21-46121563-G-T

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.1466G>A​(p.Arg489Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00125 in 1,612,800 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts 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. R489W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0058 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00077 (10 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:10
• Conservation: PhyloP100: 5.63
• Publications: 4 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=0.011221677).
• BP6: Variant 21-46121563-G-A is Benign according to our data. Variant chr21-46121563-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00583 (888/152290) while in subpopulation AFR AF = 0.0188 (782/41560). AF 95% confidence interval is 0.0177. There are 5 homozygotes in GnomAd4. There are 419 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.1466G>A	p.Arg489Gln	missense	Exon 18 of 28	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.1466G>A	p.Arg489Gln	missense	Exon 18 of 28	NP_478054.2	P12110-2
	COL6A2	NM_058175.3		c.1466G>A	p.Arg489Gln	missense	Exon 18 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.1466G>A	p.Arg489Gln	missense	Exon 18 of 28	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.1466G>A	p.Arg489Gln	missense	Exon 18 of 28	ENSP00000380870.1	P12110-2
	COL6A2	ENST00000857098.1		c.1661G>A	p.Arg554Gln	missense	Exon 18 of 28	ENSP00000527157.1

Frequencies

GnomAD3 genomes AF: 0.00583 AC: 887 AN: 152172 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00464

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00909

GnomAD2 exomes AF: 0.00174 AC: 435 AN: 249766 AF XY: 0.00134

Gnomad AFR exome AF: 0.0186

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000374

Gnomad OTH exome AF: 0.000819

GnomAD4 exome AF: 0.000772 AC: 1127 AN: 1460510 Hom.: 10 Cov.: 32 AF XY: 0.000669 AC XY: 486 AN XY: 726562

African (AFR) AF: 0.0182 AC: 610 AN: 33478

American (AMR) AF: 0.00293 AC: 131 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52170

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5762

European-Non Finnish (NFE) AF: 0.000219 AC: 244 AN: 1111930

Other (OTH) AF: 0.00194 AC: 117 AN: 60374

GnomAD4 genome AF: 0.00583 AC: 888 AN: 152290 Hom.: 5 Cov.: 33 AF XY: 0.00563 AC XY: 419 AN XY: 74466

African (AFR) AF: 0.0188 AC: 782 AN: 41560

American (AMR) AF: 0.00464 AC: 71 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68018

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.00161 Hom.: 5

Bravo AF: 0.00667

ESP6500AA AF: 0.0168 AC: 74

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00190 AC: 230

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
1	-	1	Bethlem myopathy 1A (2)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	Myosclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.087	D
MutationAssessor	Benign	0.83	L
PhyloP100		5.6
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.35
Sift	Benign	0.19	T
Sift4G	Benign	0.32	T
Polyphen		1.0	D
Vest4		0.59
MVP		0.95
MPC		0.22
ClinPred		0.022	T
GERP RS		4.2
Varity_R		0.16
gMVP		0.33
Mutation Taster		=99/1	disease causing (ClinVar)

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: rs61735828; hg19: chr21-47541477; COSMIC: COSV55999219; COSMIC: COSV55999219;