rs111231885

Variant names:

• chr2-237368568-C-T
• rs111231885
• NM_004369.4:c.4895G>A
• COL6A3 p.Arg1632Gln

Your query was ambiguous. Multiple possible variants found:

• chr2-237368568-C-T
• chr2-237368568-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_004369.4(COL6A3):​c.4895G>A​(p.Arg1632Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00506 in 1,614,030 control chromosomes in the GnomAD database, including 144 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. R1632W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0057 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (128 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.909
• Publications: 12 publications found

Genes affected

COL6A3 (HGNC:2213): (collagen type VI alpha 3 chain) This gene encodes the alpha-3 chain, one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The alpha-3 chain of type VI collagen is much larger than the alpha-1 and -2 chains. This difference in size is largely due to an increase in the number of subdomains, similar to von Willebrand Factor type A domains, that are found in the amino terminal globular domain of all the alpha chains. 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 the type VI collagen genes are associated with Bethlem myopathy, a rare autosomal dominant proximal myopathy with early childhood onset. Mutations in this gene are also a cause of Ullrich congenital muscular dystrophy, also referred to as Ullrich scleroatonic muscular dystrophy, an autosomal recessive congenital myopathy that is more severe than Bethlem myopathy. Multiple transcript variants have been identified, but the full-length nature of only some of these variants has been described. [provided by RefSeq, Jun 2009]

COL6A3 Gene-Disease associations (from GenCC):

• Bethlem myopathy 1A

  Inheritance: AD, SD, AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
• Ullrich congenital muscular dystrophy 1C

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• collagen 6-related myopathy

  Inheritance: SD, AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• dystonia 27

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: ClinGen, Orphanet, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AR, AD, SD Classification: STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Bethlem myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ullrich congenital muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003070861).
• BP6: Variant 2-237368568-C-T is Benign according to our data. Variant chr2-237368568-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00569 (866/152174) while in subpopulation EAS AF = 0.0385 (199/5174). AF 95% confidence interval is 0.0341. There are 16 homozygotes in GnomAd4. There are 576 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR,AD,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004369.4. 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
	COL6A3	NM_004369.4	MANE Select	c.4895G>A	p.Arg1632Gln	missense	Exon 10 of 44	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.4277G>A	p.Arg1426Gln	missense	Exon 9 of 43	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.3074G>A	p.Arg1025Gln	missense	Exon 7 of 41	NP_476507.3	P12111-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.4895G>A	p.Arg1632Gln	missense	Exon 10 of 44	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.3074G>A	p.Arg1025Gln	missense	Exon 7 of 41	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000353578.9	TSL:5	c.4277G>A	p.Arg1426Gln	missense	Exon 9 of 43	ENSP00000315873.4	P12111-2

Frequencies

GnomAD3 genomes AF: 0.00571 AC: 868 AN: 152058 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0386

Gnomad SAS AF: 0.0309

Gnomad FIN AF: 0.0340

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.0101 AC: 2537 AN: 251206 AF XY: 0.0113

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.0360

Gnomad FIN exome AF: 0.0286

Gnomad NFE exome AF: 0.00196

Gnomad OTH exome AF: 0.00750

GnomAD4 exome AF: 0.00499 AC: 7296 AN: 1461856 Hom.: 128 Cov.: 33 AF XY: 0.00572 AC XY: 4163 AN XY: 727226

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.000783 AC: 35 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 27 AN: 26136

East Asian (EAS) AF: 0.0371 AC: 1472 AN: 39698

South Asian (SAS) AF: 0.0284 AC: 2452 AN: 86252

European-Finnish (FIN) AF: 0.0266 AC: 1420 AN: 53420

Middle Eastern (MID) AF: 0.00954 AC: 55 AN: 5768

European-Non Finnish (NFE) AF: 0.00119 AC: 1326 AN: 1111982

Other (OTH) AF: 0.00813 AC: 491 AN: 60396

GnomAD4 genome AF: 0.00569 AC: 866 AN: 152174 Hom.: 16 Cov.: 32 AF XY: 0.00774 AC XY: 576 AN XY: 74378

African (AFR) AF: 0.000265 AC: 11 AN: 41512

American (AMR) AF: 0.00111 AC: 17 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.0385 AC: 199 AN: 5174

South Asian (SAS) AF: 0.0310 AC: 149 AN: 4812

European-Finnish (FIN) AF: 0.0340 AC: 361 AN: 10604

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00156 AC: 106 AN: 67994

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00307 Hom.: 14

Bravo AF: 0.00272

Asia WGS AF: 0.0500 AC: 174 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00124

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	Ullrich congenital muscular dystrophy 1A;C4225336:Dystonia 27;CN029274:Bethlem myopathy 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.4
DANN	Benign	0.68
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.91
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.14
Sift	Benign	0.30	T
Sift4G	Benign	0.14	T
Varity_R		0.045
gMVP		0.27
Mutation Taster		=99/1	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs111231885;

hg19: chr2-238277211;

COSMIC: COSV55094155;

COSMIC: COSV55094155;