chr2-237368614-C-G

Variant names:

• chr2-237368614-C-G
• rs200433282
• NM_004369.4:c.4849G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004369.4(COL6A3):​c.4849G>C​(p.Ala1617Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1617T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.408
• Publications: 4 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: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
• collagen 6-related myopathy

  Inheritance: AR, SD, AD 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics, Illumina
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AR, AD, SD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0054544806).

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.4849G>C	p.Ala1617Pro	missense	Exon 10 of 44	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.4231G>C	p.Ala1411Pro	missense	Exon 9 of 43	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.3028G>C	p.Ala1010Pro	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.4849G>C	p.Ala1617Pro	missense	Exon 10 of 44	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.3028G>C	p.Ala1010Pro	missense	Exon 7 of 41	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000353578.9	TSL:5	c.4231G>C	p.Ala1411Pro	missense	Exon 9 of 43	ENSP00000315873.4	P12111-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.000960 AC: 239 AN: 249002 AF XY: 0.000725

Gnomad AFR exome AF: 0.00439

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.000598

Gnomad EAS exome AF: 0.000714

Gnomad FIN exome AF: 0.00164

Gnomad NFE exome AF: 0.000968

Gnomad OTH exome AF: 0.000830

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000105 AC: 153 AN: 1461134 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 78 AN XY: 726876

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00225 AC: 119 AN: 52908

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111904

Other (OTH) AF: 0.000249 AC: 15 AN: 60272

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00768 AC: 933

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	8.9
DANN	Benign	0.56
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	-0.69	N
PhyloP100		0.41
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.11
Sift	Benign	0.31	T
Sift4G	Benign	0.17	T
Polyphen		0.013	B
Vest4		0.14
MVP		0.72
MPC		0.41
ClinPred		0.010	T
GERP RS		1.6
Varity_R		0.097
gMVP		0.46
Mutation Taster		=87/13	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: rs200433282; hg19: chr2-238277257;