rs535007570

Variant names:

• chr21-46120518-G-A
• rs535007570
• NM_001849.4:c.1336G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-46120518-G-A
• chr21-46120518-G-C
• chr21-46120518-G-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_001849.4(COL6A2):​c.1336G>A​(p.Asp446Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000881 in 1,507,332 control chromosomes in the GnomAD database, including 1 homozygotes. 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. D446H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00092 (1 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:6 O:1
• Conservation: PhyloP100: 6.86
• Publications: 5 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 21-46120518-G-A is Benign according to our data. Variant chr21-46120518-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194621.

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.1336G>A	p.Asp446Asn	missense	Exon 16 of 28	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.1336G>A	p.Asp446Asn	missense	Exon 16 of 28	NP_478054.2	P12110-2
	COL6A2	NM_058175.3		c.1336G>A	p.Asp446Asn	missense	Exon 16 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.1336G>A	p.Asp446Asn	missense	Exon 16 of 28	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.1336G>A	p.Asp446Asn	missense	Exon 16 of 28	ENSP00000380870.1	P12110-2
	COL6A2	ENST00000857098.1		c.1531G>A	p.Asp511Asn	missense	Exon 16 of 28	ENSP00000527157.1

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152176 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000418 AC: 45 AN: 107528 AF XY: 0.000404

Gnomad AFR exome AF: 0.000145

Gnomad AMR exome AF: 0.0000663

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000751

Gnomad NFE exome AF: 0.000815

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000916 AC: 1241 AN: 1355156 Hom.: 1 Cov.: 32 AF XY: 0.000884 AC XY: 590 AN XY: 667224

African (AFR) AF: 0.000239 AC: 7 AN: 29252

American (AMR) AF: 0.0000777 AC: 2 AN: 25740

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22122

East Asian (EAS) AF: 0.00 AC: 0 AN: 34838

South Asian (SAS) AF: 0.00 AC: 0 AN: 73062

European-Finnish (FIN) AF: 0.000642 AC: 30 AN: 46708

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5030

European-Non Finnish (NFE) AF: 0.00112 AC: 1185 AN: 1062584

Other (OTH) AF: 0.000305 AC: 17 AN: 55820

GnomAD4 genome AF: 0.000572 AC: 87 AN: 152176 Hom.: 0 Cov.: 34 AF XY: 0.000457 AC XY: 34 AN XY: 74338

African (AFR) AF: 0.000362 AC: 15 AN: 41438

American (AMR) AF: 0.000262 AC: 4 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.000376 AC: 4 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000897 AC: 61 AN: 68006

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.000446

ExAC AF: 0.0000966 AC: 5

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	2	not provided (5)
-	1	1	not specified (2)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Collagen 6-related myopathy (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	Myosclerosis (1)
-	1	-	Ullrich congenital muscular dystrophy 1A (1)
-	-	-	Ullrich congenital muscular dystrophy 1A;CN029274:Bethlem myopathy 1A;CN117976:Collagen 6-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	1.6	L
PhyloP100		6.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.59
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.041	D
Polyphen		1.0	D
Vest4		0.44
MVP		0.97
MPC		0.15
ClinPred		0.27	T
GERP RS		4.4
PromoterAI		0.032	Neutral
Varity_R		0.19
gMVP		0.12
Mutation Taster		=76/24	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: rs535007570; hg19: chr21-47540432; COSMIC: COSV56004026; COSMIC: COSV56004026;