rs117725825

Variant names:

• chr21-46132287-C-T
• rs117725825
• NM_001849.4:c.2795C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-46132287-C-T
• chr21-46132287-C-A
• chr21-46132287-C-G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_001849.4(COL6A2):​c.2795C>T​(p.Pro932Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00345 in 1,606,806 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P932P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0024 (3 hom., cov: 34)
  • Exomes 𝑓: 0.0036 (11 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:9 O:1
• Conservation: PhyloP100: 1.14
• Publications: 14 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.34583524).
• BP6: Variant 21-46132287-C-T is Benign according to our data. Variant chr21-46132287-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 17164.
• BS2: High Homozygotes in GnomAd4 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.2795C>T	p.Pro932Leu	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.2795C>T	p.Pro932Leu	missense	Exon 28 of 28	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000857098.1		c.2990C>T	p.Pro997Leu	missense	Exon 28 of 28	ENSP00000527157.1
	COL6A2	ENST00000857103.1		c.2957C>T	p.Pro986Leu	missense	Exon 28 of 28	ENSP00000527162.1

Frequencies

GnomAD3 genomes AF: 0.00236 AC: 359 AN: 152218 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00420

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00247 AC: 590 AN: 238806 AF XY: 0.00274

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.00137

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00167

Gnomad NFE exome AF: 0.00393

Gnomad OTH exome AF: 0.00186

GnomAD4 exome AF: 0.00357 AC: 5193 AN: 1454470 Hom.: 11 Cov.: 34 AF XY: 0.00351 AC XY: 2543 AN XY: 723836

African (AFR) AF: 0.000628 AC: 21 AN: 33436

American (AMR) AF: 0.00126 AC: 56 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.00205 AC: 176 AN: 85984

European-Finnish (FIN) AF: 0.00179 AC: 85 AN: 47588

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5760

European-Non Finnish (NFE) AF: 0.00421 AC: 4673 AN: 1111234

Other (OTH) AF: 0.00277 AC: 167 AN: 60256

GnomAD4 genome AF: 0.00235 AC: 358 AN: 152336 Hom.: 3 Cov.: 34 AF XY: 0.00189 AC XY: 141 AN XY: 74486

African (AFR) AF: 0.000746 AC: 31 AN: 41574

American (AMR) AF: 0.000457 AC: 7 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4830

European-Finnish (FIN) AF: 0.000941 AC: 10 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00419 AC: 285 AN: 68030

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00303 Hom.: 7

Bravo AF: 0.00229

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00232 AC: 280

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Bethlem myopathy 1A (3)
-	1	2	not provided (3)
-	-	2	not specified (2)
1	-	-	Bethlem myopathy 1B (1)
-	-	1	COL6A2-related disorder (1)
-	-	1	Collagen 6-related myopathy (2)
-	-	1	Myosclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	16
DANN	Benign	0.66
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.1
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.040	N
REVEL	Uncertain	0.46
Sift	Benign	0.65	T
Sift4G	Benign	0.64	T
Polyphen		0.13	B
Vest4		0.68
MVP		0.82
MPC		0.15
ClinPred		0.0098	T
GERP RS		3.2
Varity_R		0.025
gMVP		0.64
Mutation Taster		=95/5	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: rs117725825; hg19: chr21-47552201;