rs141166141

Variant names:

• chr21-46122138-C-T
• rs141166141
• NM_001849.4:c.1552C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-46122138-C-T
• chr21-46122138-C-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.1552C>T​(p.Pro518Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,612,736 control chromosomes in the GnomAD database, including 181 homozygotes. In-silico tool predicts 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. P518R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0095 (9 hom., cov: 32)
  • Exomes 𝑓: 0.014 (172 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 3.58
• 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=0.01017496).
• BP6: Variant 21-46122138-C-T is Benign according to our data. Variant chr21-46122138-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00947 (1442/152288) while in subpopulation NFE AF = 0.0159 (1080/68020). AF 95% confidence interval is 0.0151. There are 9 homozygotes in GnomAd4. There are 654 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.1552C>T	p.Pro518Ser	missense	Exon 19 of 28	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.1552C>T	p.Pro518Ser	missense	Exon 19 of 28	NP_478054.2	P12110-2
	COL6A2	NM_058175.3		c.1552C>T	p.Pro518Ser	missense	Exon 19 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.1552C>T	p.Pro518Ser	missense	Exon 19 of 28	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.1552C>T	p.Pro518Ser	missense	Exon 19 of 28	ENSP00000380870.1	P12110-2
	COL6A2	ENST00000857098.1		c.1747C>T	p.Pro583Ser	missense	Exon 19 of 28	ENSP00000527157.1

Frequencies

GnomAD3 genomes AF: 0.00948 AC: 1442 AN: 152170 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00294

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00903

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00508

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00882 AC: 2196 AN: 248978 AF XY: 0.00888

Gnomad AFR exome AF: 0.00212

Gnomad AMR exome AF: 0.00550

Gnomad ASJ exome AF: 0.00671

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00453

Gnomad NFE exome AF: 0.0155

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.0136 AC: 19920 AN: 1460448 Hom.: 172 Cov.: 33 AF XY: 0.0133 AC XY: 9638 AN XY: 726498

African (AFR) AF: 0.00218 AC: 73 AN: 33480

American (AMR) AF: 0.00620 AC: 277 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00712 AC: 186 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86242

European-Finnish (FIN) AF: 0.00597 AC: 311 AN: 52086

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0165 AC: 18302 AN: 1111962

Other (OTH) AF: 0.0123 AC: 740 AN: 60370

GnomAD4 genome AF: 0.00947 AC: 1442 AN: 152288 Hom.: 9 Cov.: 32 AF XY: 0.00878 AC XY: 654 AN XY: 74464

African (AFR) AF: 0.00294 AC: 122 AN: 41552

American (AMR) AF: 0.00902 AC: 138 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00508 AC: 54 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0159 AC: 1080 AN: 68020

Other (OTH) AF: 0.0128 AC: 27 AN: 2112

Alfa AF: 0.0136 Hom.: 46

Bravo AF: 0.00993

TwinsUK AF: 0.0159 AC: 59

ALSPAC AF: 0.0158 AC: 61

ESP6500AA AF: 0.00387 AC: 17

ESP6500EA AF: 0.0156 AC: 134

ExAC AF: 0.00879 AC: 1064

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0140

EpiControl AF: 0.0129

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	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	0.16
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		3.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.067	T
Polyphen		1.0	D
Vest4		0.63
MVP		0.99
MPC		0.27
ClinPred		0.024	T
GERP RS		4.5
Varity_R		0.31
gMVP		0.42
Mutation Taster		=96/4	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: rs141166141; hg19: chr21-47542052; COSMIC: COSV106095870; COSMIC: COSV106095870;