rs141021828

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001849.4(COL6A2):​c.2605G>A​(p.Asp869Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00036 in 1,595,502 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., cov: 34)
Exomes 𝑓: 0.00022 ( 3 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

19

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.24
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0058701932).
BP6
Variant 21-46132097-G-A is Benign according to our data. Variant chr21-46132097-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 166935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000215 (311/1443218) while in subpopulation AFR AF= 0.00806 (266/33022). AF 95% confidence interval is 0.00726. There are 3 homozygotes in gnomad4_exome. There are 129 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL6A2NM_001849.4 linkc.2605G>A p.Asp869Asn missense_variant Exon 28 of 28 ENST00000300527.9 NP_001840.3 P12110-1A0A384MDP3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL6A2ENST00000300527.9 linkc.2605G>A p.Asp869Asn missense_variant Exon 28 of 28 1 NM_001849.4 ENSP00000300527.4 P12110-1

Frequencies

GnomAD3 genomes
AF:
0.00173
AC:
263
AN:
152166
Hom.:
1
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00611
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000458
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:
0.000955
GnomAD3 exomes
AF:
0.000427
AC:
90
AN:
210720
Hom.:
0
AF XY:
0.000327
AC XY:
38
AN XY:
116084
show subpopulations
Gnomad AFR exome
AF:
0.00622
Gnomad AMR exome
AF:
0.000286
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000358
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000185
GnomAD4 exome
AF:
0.000215
AC:
311
AN:
1443218
Hom.:
3
Cov.:
33
AF XY:
0.000180
AC XY:
129
AN XY:
717496
show subpopulations
Gnomad4 AFR exome
AF:
0.00806
Gnomad4 AMR exome
AF:
0.000351
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000237
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000118
Gnomad4 OTH exome
AF:
0.000218
GnomAD4 genome
AF:
0.00173
AC:
264
AN:
152284
Hom.:
1
Cov.:
34
AF XY:
0.00171
AC XY:
127
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.00611
Gnomad4 AMR
AF:
0.000458
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:
0.000945
Alfa
AF:
0.000102
Hom.:
0
Bravo
AF:
0.00177
ExAC
AF:
0.000494
AC:
59

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Jan 28, 2021
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge -

Jul 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

COL6A2: BP4, BS2 -

not specified Benign:1
Feb 20, 2015
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Myosclerosis Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Collagen 6-related myopathy Benign:1
Jan 12, 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. -

Bethlem myopathy 1A Benign:1
Jan 12, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
18
DANN
Benign
0.77
DEOGEN2
Benign
0.18
T
Eigen
Benign
-0.79
Eigen_PC
Benign
-0.79
FATHMM_MKL
Benign
0.17
N
LIST_S2
Benign
0.71
T
M_CAP
Benign
0.031
D
MetaRNN
Benign
0.0059
T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
0.17
N
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-0.040
N
REVEL
Benign
0.12
Sift
Benign
0.56
T
Sift4G
Benign
0.50
T
Polyphen
0.0030
B
Vest4
0.17
MVP
0.81
MPC
0.14
ClinPred
0.0034
T
GERP RS
3.2
Varity_R
0.057
gMVP
0.53

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs141021828; hg19: chr21-47552011; API