rs141233891

Variant names:

• chr21-46132175-A-C
• rs141233891
• NM_001849.4:c.2683A>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001849.4(COL6A2):​c.2683A>C​(p.Ser895Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00177 in 1,572,704 control chromosomes in the GnomAD database, including 5 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. S895N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0018 (4 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.09
• Publications: 8 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008235663).
• BP6: Variant 21-46132175-A-C is Benign according to our data. Variant chr21-46132175-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 196119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.2683A>C	p.Ser895Arg	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.2683A>C	p.Ser895Arg	missense	Exon 28 of 28	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000857098.1		c.2878A>C	p.Ser960Arg	missense	Exon 28 of 28	ENSP00000527157.1
	COL6A2	ENST00000857103.1		c.2845A>C	p.Ser949Arg	missense	Exon 28 of 28	ENSP00000527162.1

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 187 AN: 152164 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00234

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00128 AC: 231 AN: 180392 AF XY: 0.00142

Gnomad AFR exome AF: 0.000295

Gnomad AMR exome AF: 0.000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000644

Gnomad NFE exome AF: 0.00192

Gnomad OTH exome AF: 0.000206

GnomAD4 exome AF: 0.00183 AC: 2595 AN: 1420422 Hom.: 4 Cov.: 33 AF XY: 0.00182 AC XY: 1281 AN XY: 703550

African (AFR) AF: 0.000155 AC: 5 AN: 32334

American (AMR) AF: 0.000364 AC: 14 AN: 38506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25428

East Asian (EAS) AF: 0.00 AC: 0 AN: 36840

South Asian (SAS) AF: 0.00196 AC: 161 AN: 81968

European-Finnish (FIN) AF: 0.000124 AC: 6 AN: 48388

Middle Eastern (MID) AF: 0.00140 AC: 8 AN: 5726

European-Non Finnish (NFE) AF: 0.00211 AC: 2310 AN: 1092350

Other (OTH) AF: 0.00155 AC: 91 AN: 58882

GnomAD4 genome AF: 0.00123 AC: 188 AN: 152282 Hom.: 1 Cov.: 34 AF XY: 0.00110 AC XY: 82 AN XY: 74476

African (AFR) AF: 0.000337 AC: 14 AN: 41560

American (AMR) AF: 0.000196 AC: 3 AN: 15304

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00234 AC: 159 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00161 Hom.: 0

Bravo AF: 0.00108

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000689 AC: 3

ESP6500EA AF: 0.00164 AC: 14

ExAC AF: 0.00106 AC: 127

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.072
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.90	L
PhyloP100		4.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.29
Sift	Benign	0.54	T
Sift4G	Benign	0.52	T
Polyphen		0.21	B
Vest4		0.29
MutPred		0.20		Gain of solvent accessibility (P = 0.204)
MVP		0.88
MPC		0.20
ClinPred		0.023	T
GERP RS		4.2
Varity_R		0.14
gMVP		0.74
Mutation Taster		=74/26	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: rs141233891; hg19: chr21-47552089;