21-46112542-G-A

Variant names:

• chr21-46112542-G-A
• rs35881321
• NM_001849.4:c.679G>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.679G>A​(p.Asp227Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0257 in 1,611,910 control chromosomes in the GnomAD database, including 622 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. D227E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.026 (69 hom., cov: 32)
  • Exomes 𝑓: 0.026 (553 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.04
• Publications: 16 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=0.003347218).
• BP6: Variant 21-46112542-G-A is Benign according to our data. Variant chr21-46112542-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93956.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 = 0.0263 (3994/152068) while in subpopulation AFR AF = 0.0319 (1323/41468). AF 95% confidence interval is 0.0305. There are 69 homozygotes in GnomAd4. There are 1881 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 69 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.679G>A	p.Asp227Asn	missense	Exon 3 of 28	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.679G>A	p.Asp227Asn	missense	Exon 3 of 28	NP_478054.2	P12110-2
	COL6A2	NM_058175.3		c.679G>A	p.Asp227Asn	missense	Exon 3 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.679G>A	p.Asp227Asn	missense	Exon 3 of 28	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.679G>A	p.Asp227Asn	missense	Exon 3 of 28	ENSP00000380870.1	P12110-2
	COL6A2	ENST00000857098.1		c.679G>A	p.Asp227Asn	missense	Exon 3 of 28	ENSP00000527157.1

Frequencies

GnomAD3 genomes AF: 0.0262 AC: 3988 AN: 151950 Hom.: 69 Cov.: 32

Gnomad AFR AF: 0.0319

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0305

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.00509

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0279

Gnomad OTH AF: 0.0389

GnomAD2 exomes AF: 0.0212 AC: 5195 AN: 244682 AF XY: 0.0212

Gnomad AFR exome AF: 0.0305

Gnomad AMR exome AF: 0.0250

Gnomad ASJ exome AF: 0.0211

Gnomad EAS exome AF: 0.000165

Gnomad FIN exome AF: 0.00581

Gnomad NFE exome AF: 0.0269

Gnomad OTH exome AF: 0.0269

GnomAD4 exome AF: 0.0257 AC: 37489 AN: 1459842 Hom.: 553 Cov.: 34 AF XY: 0.0254 AC XY: 18454 AN XY: 726296

African (AFR) AF: 0.0294 AC: 985 AN: 33466

American (AMR) AF: 0.0248 AC: 1108 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 557 AN: 26118

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39660

South Asian (SAS) AF: 0.0150 AC: 1291 AN: 86234

European-Finnish (FIN) AF: 0.00701 AC: 362 AN: 51676

Middle Eastern (MID) AF: 0.0291 AC: 168 AN: 5768

European-Non Finnish (NFE) AF: 0.0284 AC: 31534 AN: 1111858

Other (OTH) AF: 0.0245 AC: 1478 AN: 60358

GnomAD4 genome AF: 0.0263 AC: 3994 AN: 152068 Hom.: 69 Cov.: 32 AF XY: 0.0253 AC XY: 1881 AN XY: 74342

African (AFR) AF: 0.0319 AC: 1323 AN: 41468

American (AMR) AF: 0.0305 AC: 466 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5154

South Asian (SAS) AF: 0.0142 AC: 68 AN: 4804

European-Finnish (FIN) AF: 0.00509 AC: 54 AN: 10616

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0279 AC: 1899 AN: 67956

Other (OTH) AF: 0.0385 AC: 81 AN: 2106

Alfa AF: 0.0265 Hom.: 123

Bravo AF: 0.0276

TwinsUK AF: 0.0237 AC: 88

ALSPAC AF: 0.0257 AC: 99

ESP6500AA AF: 0.0266 AC: 117

ESP6500EA AF: 0.0274 AC: 235

ExAC AF: 0.0205 AC: 2492

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.0288

EpiControl AF: 0.0298

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	not provided (4)
-	-	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	0.069
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.0
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.13
Sift	Benign	0.51	T
Sift4G	Benign	0.69	T
Polyphen		0.42	B
Vest4		0.35
MPC		0.13
ClinPred		0.0055	T
GERP RS		3.2
Varity_R		0.11
gMVP		0.61
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35881321; hg19: chr21-47532456; COSMIC: COSV56003036; COSMIC: COSV56003036;