Genetic Variant NM_001849.4:c.981C>G (chr21-46116796-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. 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. Synonymous variant affecting the same amino acid position (i.e. N327N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.91

Publications

2 publications found

Variant links:

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]

COL6A2 Gene-Disease associations (from GenCC):

collagen 6-related myopathy
Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
Ullrich congenital muscular dystrophy 1B
Inheritance: AR, AD Classification: DEFINITIVE Submitted by: G2P
Bethlem myopathy 1A
Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
Ullrich congenital muscular dystrophy 1A
Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Bethlem myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Ullrich congenital muscular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
myosclerosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

COL6A2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
COL6A2	NM_001849.4 link	c.981C>G	p.Asn327Lys	missense_variant	Exon 10 of 28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3 link	c.981C>G	p.Asn327Lys	missense_variant	Exon 10 of 28	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3 link	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
COL6A2	ENST00000300527.9 link	c.981C>G	p.Asn327Lys	missense_variant	Exon 10 of 28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6 link	c.981C>G	p.Asn327Lys	missense_variant	Exon 10 of 28	5	NM_058174.3	ENSP00000380870.1
COL6A2	ENST00000409416.6 link	c.981C>G	p.Asn327Lys	missense_variant	Exon 9 of 27	5		ENSP00000387115.1
COL6A2	ENST00000485591.1 link	n.637C>G		non_coding_transcript_exon_variant	Exon 6 of 7	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

250110

AF XY:

0.00000737

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460696

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726638

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111986

Other (OTH)

AF:

0.00

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

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

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.39

T;.;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.77

T;T;.;T

M_CAP

Pathogenic

0.77

MetaRNN

Uncertain

0.56

D;D;D;D

MetaSVM

Uncertain

-0.028

MutationAssessor

Benign

0.57

N;N;N;N

PhyloP100

-1.9

PrimateAI

Uncertain

0.74

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

GERP RS

-7.3

Varity_R

0.36

gMVP

0.76

Mutation Taster

=63/37

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over