chr21-46116796-C-G

Variant names:

• chr21-46116796-C-G
• rs768836349
• NM_001849.4:c.981C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001849.4(COL6A2):​c.981C>G​(p.Asn327Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,696 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.91

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 4 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity CO6A2_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.981C>G	p.Asn327Lys	missense_variant	Exon 10 of 28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.981C>G	p.Asn327Lys	missense_variant	Exon 10 of 28		NP_478054.2
COL6A2	NM_058175.3	c.981C>G	p.Asn327Lys	missense_variant	Exon 10 of 28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.981C>G	p.Asn327Lys	missense_variant	Exon 10 of 28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.981C>G	p.Asn327Lys	missense_variant	Exon 10 of 28	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.981C>G	p.Asn327Lys	missense_variant	Exon 9 of 27	5		ENSP00000387115.1
COL6A2	ENST00000485591.1	n.637C>G		non_coding_transcript_exon_variant	Exon 6 of 7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250110 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135674

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460696 Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 2 AN XY: 726638

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	15
DANN	Benign	0.87
DEOGEN2	Benign	0.39	T;.;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.77	T;T;.;T
M_CAP	Pathogenic	0.77	D
MetaRNN	Uncertain	0.56	D;D;D;D
MetaSVM	Uncertain	-0.028	T
MutationAssessor	Benign	0.57	N;N;N;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.7	D;N;N;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.021	D;D;D;D
Sift4G	Benign	0.068	T;T;T;T
Polyphen		1.0	D;B;B;D
Vest4		0.72
MutPred		0.26		Gain of glycosylation at N327 (P = 0.0044);Gain of glycosylation at N327 (P = 0.0044);Gain of glycosylation at N327 (P = 0.0044);Gain of glycosylation at N327 (P = 0.0044);
MVP		0.63
MPC		0.21
ClinPred		0.53	D
GERP RS		-7.3
Varity_R		0.36
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs768836349; hg19: chr21-47536710;