NM_001849.4:c.2803G>A

Variant names:

• chr21-46132295-G-A
• rs35548026
• NM_001849.4:c.2803G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001849.4(COL6A2):​c.2803G>A​(p.Gly935Arg) variant causes a missense change. The variant allele was found at a frequency of 0.084 in 1,605,536 control chromosomes in the GnomAD database, including 5,894 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. G935E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.080 (487 hom., cov: 34)
  • Exomes 𝑓: 0.084 (5407 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 4.63
• Publications: 20 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002195537).
• BP6: Variant 21-46132295-G-A is Benign according to our data. Variant chr21-46132295-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0884 is higher than 0.05.

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.2803G>A	p.Gly935Arg	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.2803G>A	p.Gly935Arg	missense	Exon 28 of 28	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000857098.1		c.2998G>A	p.Gly1000Arg	missense	Exon 28 of 28	ENSP00000527157.1
	COL6A2	ENST00000857103.1		c.2965G>A	p.Gly989Arg	missense	Exon 28 of 28	ENSP00000527162.1

Frequencies

GnomAD3 genomes AF: 0.0804 AC: 12233 AN: 152076 Hom.: 487 Cov.: 34

Gnomad AFR AF: 0.0748

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.0925

Gnomad ASJ AF: 0.0828

Gnomad EAS AF: 0.0544

Gnomad SAS AF: 0.0496

Gnomad FIN AF: 0.0825

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0843

Gnomad OTH AF: 0.0903

GnomAD2 exomes AF: 0.0793 AC: 18809 AN: 237052 AF XY: 0.0789

Gnomad AFR exome AF: 0.0783

Gnomad AMR exome AF: 0.0748

Gnomad ASJ exome AF: 0.0828

Gnomad EAS exome AF: 0.0602

Gnomad FIN exome AF: 0.0846

Gnomad NFE exome AF: 0.0879

Gnomad OTH exome AF: 0.0808

GnomAD4 exome AF: 0.0844 AC: 122592 AN: 1453342 Hom.: 5407 Cov.: 36 AF XY: 0.0838 AC XY: 60645 AN XY: 723282

African (AFR) AF: 0.0804 AC: 2689 AN: 33426

American (AMR) AF: 0.0756 AC: 3363 AN: 44472

Ashkenazi Jewish (ASJ) AF: 0.0844 AC: 2198 AN: 26036

East Asian (EAS) AF: 0.0432 AC: 1712 AN: 39598

South Asian (SAS) AF: 0.0613 AC: 5274 AN: 86002

European-Finnish (FIN) AF: 0.0861 AC: 4025 AN: 46744

Middle Eastern (MID) AF: 0.0856 AC: 493 AN: 5756

European-Non Finnish (NFE) AF: 0.0881 AC: 97940 AN: 1111084

Other (OTH) AF: 0.0813 AC: 4898 AN: 60224

GnomAD4 genome AF: 0.0804 AC: 12234 AN: 152194 Hom.: 487 Cov.: 34 AF XY: 0.0795 AC XY: 5918 AN XY: 74402

African (AFR) AF: 0.0747 AC: 3102 AN: 41532

American (AMR) AF: 0.0924 AC: 1413 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0828 AC: 287 AN: 3468

East Asian (EAS) AF: 0.0543 AC: 281 AN: 5174

South Asian (SAS) AF: 0.0493 AC: 238 AN: 4830

European-Finnish (FIN) AF: 0.0825 AC: 875 AN: 10606

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0842 AC: 5727 AN: 67980

Other (OTH) AF: 0.0899 AC: 190 AN: 2114

Alfa AF: 0.0813 Hom.: 299

Bravo AF: 0.0824

TwinsUK AF: 0.0836 AC: 310

ALSPAC AF: 0.0815 AC: 314

ESP6500AA AF: 0.0810 AC: 356

ESP6500EA AF: 0.0816 AC: 701

ExAC AF: 0.0783 AC: 9422

Asia WGS AF: 0.0540 AC: 186 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	not provided (2)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	Glutamate formiminotransferase deficiency (1)
-	-	1	Myosclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Benign	0.86
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.68	N
PhyloP100		4.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.23
Sift	Benign	0.070	T
Sift4G	Benign	0.15	T
Polyphen		0.86	P
Vest4		0.12
MutPred		0.32		Gain of methylation at G935 (P = 0.0097)
MPC		0.38
ClinPred		0.035	T
GERP RS		3.3
Varity_R		0.064
gMVP		0.81
Mutation Taster		=96/4	polymorphism (auto)

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: rs35548026; hg19: chr21-47552209; COSMIC: COSV52423033; COSMIC: COSV52423033;