rs150165484

Variant names:

• chr2-237344760-G-A
• rs150165484
• NM_004369.4:c.7258C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-237344760-G-A
• chr2-237344760-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_004369.4(COL6A3):​c.7258C>T​(p.Arg2420Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000924 in 1,601,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2420Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (0 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:3
• Conservation: PhyloP100: 1.95
• Publications: 9 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.056619078).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0009 (137/152274) while in subpopulation NFE AF = 0.00128 (87/68032). AF 95% confidence interval is 0.00106. There are 0 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	NM_004369.4	MANE Select	c.7258C>T	p.Arg2420Trp	missense	Exon 36 of 44	NP_004360.2
	COL6A3	NM_057167.4		c.6640C>T	p.Arg2214Trp	missense	Exon 35 of 43	NP_476508.2
	COL6A3	NM_057166.5		c.5437C>T	p.Arg1813Trp	missense	Exon 33 of 41	NP_476507.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.7258C>T	p.Arg2420Trp	missense	Exon 36 of 44	ENSP00000295550.4
	COL6A3	ENST00000472056.5	TSL:1	c.5437C>T	p.Arg1813Trp	missense	Exon 33 of 41	ENSP00000418285.1
	COL6A3	ENST00000353578.9	TSL:5	c.6640C>T	p.Arg2214Trp	missense	Exon 35 of 43	ENSP00000315873.4

Frequencies

GnomAD3 genomes AF: 0.000907 AC: 138 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000822 AC: 199 AN: 242156 AF XY: 0.000808

Gnomad AFR exome AF: 0.0000632

Gnomad AMR exome AF: 0.000480

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00327

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.000514

GnomAD4 exome AF: 0.000927 AC: 1343 AN: 1449176 Hom.: 0 Cov.: 34 AF XY: 0.000978 AC XY: 704 AN XY: 719878

African (AFR) AF: 0.0000304 AC: 1 AN: 32912

American (AMR) AF: 0.000599 AC: 26 AN: 43384

Ashkenazi Jewish (ASJ) AF: 0.0000392 AC: 1 AN: 25482

East Asian (EAS) AF: 0.00 AC: 0 AN: 39550

South Asian (SAS) AF: 0.0000706 AC: 6 AN: 84948

European-Finnish (FIN) AF: 0.00266 AC: 136 AN: 51166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00103 AC: 1137 AN: 1106262

Other (OTH) AF: 0.000602 AC: 36 AN: 59776

GnomAD4 genome AF: 0.000900 AC: 137 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.000954 AC XY: 71 AN XY: 74450

African (AFR) AF: 0.000241 AC: 10 AN: 41554

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00128 AC: 87 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000840 Hom.: 0

Bravo AF: 0.000604

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000684 AC: 83

EpiCase AF: 0.00104

EpiControl AF: 0.000831

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	1	1	Bethlem myopathy 1A (2)
-	-	1	Collagen 6-related myopathy (1)
1	-	-	Tip-toe gait (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Benign	0.79
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	0.11
Eigen_PC	Benign	-0.024
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.057	T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.9
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.60
MVP		0.94
MPC		0.15
ClinPred		0.11	T
GERP RS		3.3
PromoterAI		-0.066	Neutral
Varity_R		0.21
gMVP		0.62
Mutation Taster		=78/22	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: rs150165484; hg19: chr2-238253403; COSMIC: COSV55083942; COSMIC: COSV55083942;