rs143338050

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001849.4(COL6A2):c.1606G>A(p.Glu536Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,612,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

COL6A2
NM_001849.4 missense, splice_region

Scores

Splicing: ADA: 0.0003318

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 1.39

Publications

3 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06379464).

BP6

Variant 21-46122529-G-A is Benign according to our data. Variant chr21-46122529-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 476454.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
COL6A2	NM_001849.4 link	c.1606G>A	p.Glu536Lys	missense_variant, splice_region_variant	Exon 20 of 28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3 link	c.1606G>A	p.Glu536Lys	missense_variant, splice_region_variant	Exon 20 of 28	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3 link	c.1606G>A	p.Glu536Lys	missense_variant, splice_region_variant	Exon 20 of 28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
COL6A2	ENST00000300527.9 link	c.1606G>A	p.Glu536Lys	missense_variant, splice_region_variant	Exon 20 of 28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6 link	c.1606G>A	p.Glu536Lys	missense_variant, splice_region_variant	Exon 20 of 28	5	NM_058174.3	ENSP00000380870.1
COL6A2	ENST00000409416.6 link	c.1606G>A	p.Glu536Lys	missense_variant, splice_region_variant	Exon 19 of 27	5		ENSP00000387115.1
COL6A2	ENST00000413758.1 link	c.229G>A	p.Glu77Lys	missense_variant, splice_region_variant	Exon 5 of 11	3		ENSP00000395751.1

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000173

AC:

AN:

249096

AF XY:

0.000148

show subpopulations

Gnomad AFR exome

AF:

0.0000626

Gnomad AMR exome

AF:

0.000782

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000893

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000135

AC:

197

AN:

1460474

Hom.:

Cov.:

AF XY:

0.000111

AC XY:

AN XY:

726524

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.000738

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000192

AC:

AN:

52114

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000130

AC:

145

AN:

1111950

Other (OTH)

AF:

0.000215

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41544

American (AMR)

AF:

0.000131

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5128

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000234

Hom.:

Bravo

AF:

0.000128

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000173

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Oct 10, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 14, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported as a variant of uncertain significance in a patient with suspected limb-girdle muscular dystrophy (Nallamilli et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30564623) -

not specified

Uncertain:1

Jun 19, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: COL6A2 c.1606G>A (p.Glu536Lys) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be tolerated. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00017 in 249096 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in COL6A2 causing Ullrich congenital muscular dystrophy 1-AR (0.00017 vs 0.0035), allowing no conclusion about variant significance. c.1606G>A has been observed in individual suspected with congenital muscular dystrophy (Nallamilli_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Ullrich congenital muscular dystrophy 1-AR. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30564623). ClinVar contains an entry for this variant (Variation ID: 476454). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Bethlem myopathy 1A

Benign:1

Jul 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Collagen 6-related myopathy

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.23

T;.;.;.;T

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.45

LIST_S2

Uncertain

0.97

D;D;.;D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.064

T;T;T;T;T

MetaSVM

Benign

-0.37

MutationAssessor

Benign

-0.81

N;N;N;N;.

PhyloP100

1.4

PrimateAI

Uncertain

0.70

PROVEAN

Benign

0.060

N;N;N;N;N

REVEL

Uncertain

0.41

Sift

Benign

0.61

T;T;T;T;T

Sift4G

Benign

0.86

T;T;T;T;T

Polyphen

0.095

B;B;B;B;.

Vest4

0.35

MVP

0.96

MPC

0.16

ClinPred

0.045

GERP RS

4.3

Varity_R

0.074

gMVP

0.25

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00033

dbscSNV1_RF

Benign

0.016

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over