rs61735835

Variant names:

• chr21-46115902-G-A
• rs61735835
• NM_001849.4:c.832G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001849.4(COL6A2):​c.832G>A​(p.Glu278Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,612,902 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (21 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (18 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.80
• Publications: 1 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, SD Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1B

  Inheritance: AD, AR 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: 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: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001849.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.008608341).
• BP6: Variant 21-46115902-G-A is Benign according to our data. Variant chr21-46115902-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93961.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 = 0.00923 (1406/152272) while in subpopulation AFR AF = 0.0306 (1272/41558). AF 95% confidence interval is 0.0292. There are 21 homozygotes in GnomAd4. There are 685 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 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.832G>A	p.Glu278Lys	missense	Exon 6 of 28	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.832G>A	p.Glu278Lys	missense	Exon 6 of 28	NP_478054.2	P12110-2
	COL6A2	NM_058175.3		c.832G>A	p.Glu278Lys	missense	Exon 6 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.832G>A	p.Glu278Lys	missense	Exon 6 of 28	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.832G>A	p.Glu278Lys	missense	Exon 6 of 28	ENSP00000380870.1	P12110-2
	COL6A2	ENST00000857098.1		c.832G>A	p.Glu278Lys	missense	Exon 6 of 28	ENSP00000527157.1

Frequencies

GnomAD3 genomes AF: 0.00921 AC: 1401 AN: 152154 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0306

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00688

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: 0.000191

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00228 AC: 569 AN: 249318 AF XY: 0.00168

Gnomad AFR exome AF: 0.0312

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000712

Gnomad OTH exome AF: 0.000657

GnomAD4 exome AF: 0.000948 AC: 1385 AN: 1460630 Hom.: 18 Cov.: 33 AF XY: 0.000824 AC XY: 599 AN XY: 726608

African (AFR) AF: 0.0330 AC: 1106 AN: 33480

American (AMR) AF: 0.00179 AC: 80 AN: 44716

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

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

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52200

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.0000405 AC: 45 AN: 1111996

Other (OTH) AF: 0.00232 AC: 140 AN: 60378

GnomAD4 genome AF: 0.00923 AC: 1406 AN: 152272 Hom.: 21 Cov.: 32 AF XY: 0.00920 AC XY: 685 AN XY: 74458

African (AFR) AF: 0.0306 AC: 1272 AN: 41558

American (AMR) AF: 0.00687 AC: 105 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68016

Other (OTH) AF: 0.00758 AC: 16 AN: 2110

Alfa AF: 0.00412 Hom.: 15

Bravo AF: 0.0106

ESP6500AA AF: 0.0239 AC: 105

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00252 AC: 306

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0086	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.8
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.99	N
REVEL	Uncertain	0.31
Sift	Benign	0.11	T
Sift4G	Benign	0.42	T
Polyphen		0.90	P
Vest4		0.54
MVP		0.97
MPC		0.55
ClinPred		0.016	T
GERP RS		4.0
Varity_R		0.27
gMVP		0.51
Mutation Taster		=99/1	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: rs61735835; hg19: chr21-47535816;