chr2-237368614-C-G

Position:

• chr2-237368614-C-G

Variant summary

Our verdict is Likely benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.4849G>C	p.Ala1617Pro	missense_variant	10/44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.4231G>C	p.Ala1411Pro	missense_variant	9/43		NP_476508.2
COL6A3	NM_057166.5	c.3028G>C	p.Ala1010Pro	missense_variant	7/41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.4849G>C	p.Ala1617Pro	missense_variant	10/44	1	NM_004369.4	ENSP00000295550.4
COL6A3	ENST00000472056.5	c.3028G>C	p.Ala1010Pro	missense_variant	7/41	1		ENSP00000418285.1
COL6A3	ENST00000353578.9	c.4231G>C	p.Ala1411Pro	missense_variant	9/43	5		ENSP00000315873.4
COL6A3	ENST00000684597.1	c.178G>C	p.Ala60Pro	missense_variant	2/3			ENSP00000508021.1

Frequencies

GnomAD3 genomes Cov.: 32

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

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00225

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome Cov.: 32

ExAC AF: 0.00768 AC: 933

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;.;T;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.85	T;T;T;T;.
MetaRNN	Benign	0.0055	T;T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	-0.69	.;N;.;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N;N;N;.;N
REVEL	Benign	0.11
Sift	Benign	0.31	T;T;T;.;T
Sift4G	Benign	0.17	T;T;T;T;T
Polyphen		0.013	B;B;.;.;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs200433282; hg19: chr2-238277257;