chr21-46125854-G-T

Variant names:

• chr21-46125854-G-T
• rs1042917
• NM_001849.4:c.2039G>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001849.4(COL6A2):​c.2039G>T​(p.Arg680Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,612,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R680H) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.95

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 5 ACMG points.

• PM1: In a domain VWFA 2 (size 190) in uniprot entity CO6A2_HUMAN there are 17 pathogenic changes around while only 5 benign (77%) in NM_001849.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.745

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.2039G>T	p.Arg680Leu	missense_variant	Exon 26 of 28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.2039G>T	p.Arg680Leu	missense_variant	Exon 26 of 28		NP_478054.2
COL6A2	NM_058175.3	c.2039G>T	p.Arg680Leu	missense_variant	Exon 26 of 28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.2039G>T	p.Arg680Leu	missense_variant	Exon 26 of 28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.2039G>T	p.Arg680Leu	missense_variant	Exon 26 of 28	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.2039G>T	p.Arg680Leu	missense_variant	Exon 25 of 27	5		ENSP00000387115.1
COL6A2	ENST00000413758.1	c.710G>T	p.Arg237Leu	missense_variant	Exon 11 of 11	3		ENSP00000395751.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151870 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460778 Hom.: 0 Cov.: 72 AF XY: 0.00000275 AC XY: 2 AN XY: 726704

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151870 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74134

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.;.;.;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D;.;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Uncertain	2.2	M;M;M;M;.
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D
REVEL	Uncertain	0.52
Sift	Benign	0.036	D;D;D;D;T
Sift4G	Benign	0.14	T;T;T;T;D
Polyphen		1.0	D;P;P;D;.
Vest4		0.77
MutPred		0.41		Loss of solvent accessibility (P = 0.0238);Loss of solvent accessibility (P = 0.0238);Loss of solvent accessibility (P = 0.0238);Loss of solvent accessibility (P = 0.0238);.;
MVP		0.68
MPC		0.68
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.54
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1042917; hg19: chr21-47545768;