rs199929757

Variant names:

• chr21-46117890-C-G
• rs199929757
• NM_001849.4:c.1070C>G

Your query was ambiguous. Multiple possible variants found:

• chr21-46117890-C-G
• chr21-46117890-C-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS2

The NM_001849.4(COL6A2):​c.1070C>G​(p.Pro357Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,612,406 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P357L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (3 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 1.71
• Publications: 3 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 -7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 uncertain in NM_001849.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.037938148).
• BP6: Variant 21-46117890-C-G is Benign according to our data. Variant chr21-46117890-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194041.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.1070C>G	p.Pro357Arg	missense	Exon 12 of 28	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.1070C>G	p.Pro357Arg	missense	Exon 12 of 28	NP_478054.2	P12110-2
	COL6A2	NM_058175.3		c.1070C>G	p.Pro357Arg	missense	Exon 12 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.1070C>G	p.Pro357Arg	missense	Exon 12 of 28	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.1070C>G	p.Pro357Arg	missense	Exon 12 of 28	ENSP00000380870.1	P12110-2
	COL6A2	ENST00000857098.1		c.1070C>G	p.Pro357Arg	missense	Exon 12 of 28	ENSP00000527157.1

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 161 AN: 152126 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00135

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000975 AC: 241 AN: 247068 AF XY: 0.000985

Gnomad AFR exome AF: 0.0000634

Gnomad AMR exome AF: 0.00134

Gnomad ASJ exome AF: 0.00564

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00118

Gnomad OTH exome AF: 0.000997

GnomAD4 exome AF: 0.00104 AC: 1520 AN: 1460162 Hom.: 3 Cov.: 32 AF XY: 0.00104 AC XY: 754 AN XY: 726280

African (AFR) AF: 0.000120 AC: 4 AN: 33470

American (AMR) AF: 0.00119 AC: 53 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00690 AC: 180 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000465 AC: 4 AN: 86000

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52474

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5764

European-Non Finnish (NFE) AF: 0.00106 AC: 1182 AN: 1111708

Other (OTH) AF: 0.00146 AC: 88 AN: 60338

GnomAD4 genome AF: 0.00106 AC: 161 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.00116 AC XY: 86 AN XY: 74440

African (AFR) AF: 0.000265 AC: 11 AN: 41546

American (AMR) AF: 0.00183 AC: 28 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

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

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00135 AC: 92 AN: 68008

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00133 Hom.: 0

Bravo AF: 0.000941

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000456 AC: 2

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000952 AC: 115

EpiCase AF: 0.00109

EpiControl AF: 0.00137

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	COL6A2-related disorder (1)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	Myosclerosis (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	20
DANN	Benign	0.64
DEOGEN2	Uncertain	0.72	D
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.038	T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.7
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.021	D
Polyphen		0.81	P
Vest4		0.36
MVP		0.94
MPC		0.49
ClinPred		0.095	T
GERP RS		2.6
Varity_R		0.48
gMVP		0.28
Mutation Taster		=73/27	polymorphism

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: rs199929757; hg19: chr21-47537804; COSMIC: COSV56009816; COSMIC: COSV56009816;