rs146092501

Variant names:

• chr2-237371861-C-T
• rs146092501
• NM_004369.4:c.4156G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004369.4(COL6A3):​c.4156G>A​(p.Glu1386Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00544 in 1,613,472 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0057 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (54 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:11
• Conservation: PhyloP100: 1.11
• Publications: 24 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, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
• collagen 6-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1C

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• dystonia 27

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

  Inheritance: AR, AD, SD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009745866).
• BP6: Variant 2-237371861-C-T is Benign according to our data. Variant chr2-237371861-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 128819.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00571 (869/152096) while in subpopulation NFE AF = 0.00635 (432/67992). AF 95% confidence interval is 0.00586. There are 6 homozygotes in GnomAd4. There are 501 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR,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.4156G>A	p.Glu1386Lys	missense	Exon 9 of 44	NP_004360.2
	COL6A3	NM_057167.4		c.3538G>A	p.Glu1180Lys	missense	Exon 8 of 43	NP_476508.2
	COL6A3	NM_057166.5		c.2335G>A	p.Glu779Lys	missense	Exon 6 of 41	NP_476507.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.4156G>A	p.Glu1386Lys	missense	Exon 9 of 44	ENSP00000295550.4
	COL6A3	ENST00000472056.5	TSL:1	c.2335G>A	p.Glu779Lys	missense	Exon 6 of 41	ENSP00000418285.1
	COL6A3	ENST00000392004.7	TSL:1	c.3538G>A	p.Glu1180Lys	missense	Exon 8 of 8	ENSP00000375861.3

Frequencies

GnomAD3 genomes AF: 0.00572 AC: 869 AN: 151978 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000701

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00751

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00105

Gnomad FIN AF: 0.0321

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00635

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00623 AC: 1563 AN: 251020 AF XY: 0.00630

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00705

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0306

Gnomad NFE exome AF: 0.00602

Gnomad OTH exome AF: 0.00896

GnomAD4 exome AF: 0.00541 AC: 7906 AN: 1461376 Hom.: 54 Cov.: 32 AF XY: 0.00543 AC XY: 3947 AN XY: 726924

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

American (AMR) AF: 0.00159 AC: 71 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00696 AC: 182 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.000870 AC: 75 AN: 86256

European-Finnish (FIN) AF: 0.0301 AC: 1594 AN: 52910

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00509 AC: 5660 AN: 1112008

Other (OTH) AF: 0.00493 AC: 298 AN: 60394

GnomAD4 genome AF: 0.00571 AC: 869 AN: 152096 Hom.: 6 Cov.: 32 AF XY: 0.00674 AC XY: 501 AN XY: 74338

African (AFR) AF: 0.000699 AC: 29 AN: 41508

American (AMR) AF: 0.00203 AC: 31 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00751 AC: 26 AN: 3464

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5140

South Asian (SAS) AF: 0.00105 AC: 5 AN: 4778

European-Finnish (FIN) AF: 0.0321 AC: 340 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00635 AC: 432 AN: 67992

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00561 Hom.: 14

Bravo AF: 0.00292

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.00598 AC: 726

EpiCase AF: 0.00485

EpiControl AF: 0.00379

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not specified (5)
-	-	4	not provided (4)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	COL6A3-related disorder (1)
-	-	1	Collagen 6-related myopathy (1)
-	1	-	Tip-toe gait (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.1
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.53
Sift	Benign	0.19	T
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.84
MVP		0.83
MPC		0.64
ClinPred		0.030	T
GERP RS		5.6
PromoterAI		-0.0016	Neutral
Varity_R		0.25
gMVP		0.65
Mutation Taster		=80/20	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: rs146092501; hg19: chr2-238280504; COSMIC: COSV106097494;