rs781742477

Positions:

• chr21-46120539-C-G
• chr21-46120539-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001849.4(COL6A2):​c.1357C>G​(p.Arg453Gly) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.76

Genes affected

COL6A2 (HGNC:2212): (collagen type VI alpha 2 chain) This gene encodes one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The product of this gene contains several domains similar to von Willebrand Factor type A domains. 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 this gene are associated with Bethlem myopathy and Ullrich scleroatonic muscular dystrophy. Three transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1357C>G	p.Arg453Gly	missense_variant	16/28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1357C>G	p.Arg453Gly	missense_variant	16/28	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3	c.1357C>G	p.Arg453Gly	missense_variant	16/28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1357C>G	p.Arg453Gly	missense_variant	16/28	1	NM_001849.4	ENSP00000300527	P1
COL6A2	ENST00000397763.6	c.1357C>G	p.Arg453Gly	missense_variant	16/28	5	NM_058174.3	ENSP00000380870
COL6A2	ENST00000409416.6	c.1357C>G	p.Arg453Gly	missense_variant	15/27	5		ENSP00000387115
COL6A2	ENST00000413758.1			upstream_gene_variant		3		ENSP00000395751

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;.;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T;T;.;T
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Benign	1.4	L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Pathogenic	0.76
Sift	Benign	0.043	D;D;D;D
Sift4G	Benign	0.097	T;T;T;T
Polyphen		1.0	D;D;D;D
Vest4		0.57
MutPred		0.47		Loss of methylation at R453 (P = 0.0062);Loss of methylation at R453 (P = 0.0062);Loss of methylation at R453 (P = 0.0062);Loss of methylation at R453 (P = 0.0062);
MVP		0.94
MPC		0.69
ClinPred		0.98	D
GERP RS		3.4
Varity_R		0.34
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs781742477; hg19: chr21-47540453;