rs1555875759

Positions:

• chr21-46126004-T-A
• chr21-46126004-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_001849.4(COL6A2):​c.2189T>A​(p.Ile730Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.82

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 Likely_pathogenic. Variant got 8 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, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.2189T>A	p.Ile730Asn	missense_variant	26/28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.2189T>A	p.Ile730Asn	missense_variant	26/28	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3	c.2189T>A	p.Ile730Asn	missense_variant	26/28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.2189T>A	p.Ile730Asn	missense_variant	26/28	1	NM_001849.4	ENSP00000300527	P1
COL6A2	ENST00000397763.6	c.2189T>A	p.Ile730Asn	missense_variant	26/28	5	NM_058174.3	ENSP00000380870
COL6A2	ENST00000409416.6	c.2189T>A	p.Ile730Asn	missense_variant	25/27	5		ENSP00000387115

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460692 Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1 AN XY: 726624

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.75	D;.;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;.;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	4.0	H;H;H;H
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.9	D;D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.97
MutPred		0.86		Gain of catalytic residue at I730 (P = 0.0159);Gain of catalytic residue at I730 (P = 0.0159);Gain of catalytic residue at I730 (P = 0.0159);Gain of catalytic residue at I730 (P = 0.0159);
MVP		1.0
MPC		0.82
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.98
gMVP		0.99

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: rs1555875759; hg19: chr21-47545918;