rs2646254

Variant names:

• chr2-237359074-C-A
• NM_004369.4:c.6369G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-237359074-C-A
• chr2-237359074-C-G
• chr2-237359074-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004369.4(COL6A3):​c.6369G>T​(p.Leu2123Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L2123L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0350

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.6369G>T	p.Leu2123Phe	missense_variant	Exon 20 of 44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.5751G>T	p.Leu1917Phe	missense_variant	Exon 19 of 43		NP_476508.2
COL6A3	NM_057166.5	c.4548G>T	p.Leu1516Phe	missense_variant	Exon 17 of 41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.6369G>T	p.Leu2123Phe	missense_variant	Exon 20 of 44	1	NM_004369.4	ENSP00000295550.4
COL6A3	ENST00000472056.5	c.4548G>T	p.Leu1516Phe	missense_variant	Exon 17 of 41	1		ENSP00000418285.1
COL6A3	ENST00000353578.9	c.5751G>T	p.Leu1917Phe	missense_variant	Exon 19 of 43	5		ENSP00000315873.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	.;T;.;T;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.064
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.85	T;D;D;D;.
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.51	D;D;D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	1.1	.;L;.;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.1	N;N;N;.;N
REVEL	Uncertain	0.44
Sift	Benign	0.064	T;T;D;.;T
Sift4G	Uncertain	0.014	D;D;D;D;D
Polyphen		1.0	D;P;.;.;D
Vest4		0.27
MutPred		0.37		.;Loss of catalytic residue at L2123 (P = 0.0749);.;.;.;
MVP		0.90
MPC		0.34
ClinPred		0.57	D
GERP RS		4.3
Varity_R		0.15
gMVP		0.22

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-238267717;