chr2-237394807-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_004369.4(COL6A3):​c.489G>A​(p.Ala163=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,614,144 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0016 ( 2 hom. )

Consequence

COL6A3
NM_004369.4 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: -0.140
Variant links:
Genes affected
COL6A3 (HGNC:2213): (collagen type VI alpha 3 chain) This gene encodes the alpha-3 chain, one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The alpha-3 chain of type VI collagen is much larger than the alpha-1 and -2 chains. This difference in size is largely due to an increase in the number of subdomains, similar to von Willebrand Factor type A domains, that are found in the amino terminal globular domain of all the alpha chains. 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 the type VI collagen genes are associated with Bethlem myopathy, a rare autosomal dominant proximal myopathy with early childhood onset. Mutations in this gene are also a cause of Ullrich congenital muscular dystrophy, also referred to as Ullrich scleroatonic muscular dystrophy, an autosomal recessive congenital myopathy that is more severe than Bethlem myopathy. Multiple transcript variants have been identified, but the full-length nature of only some of these variants has been described. [provided by RefSeq, Jun 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.68).
BP6
Variant 2-237394807-C-T is Benign according to our data. Variant chr2-237394807-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 259302.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}.
BP7
Synonymous conserved (PhyloP=-0.14 with no splicing effect.
BS2
High Homozygotes in GnomAdExome4 at 2 SD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL6A3NM_004369.4 linkuse as main transcriptc.489G>A p.Ala163= synonymous_variant 3/44 ENST00000295550.9 NP_004360.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL6A3ENST00000295550.9 linkuse as main transcriptc.489G>A p.Ala163= synonymous_variant 3/441 NM_004369.4 ENSP00000295550 P1P12111-1

Frequencies

GnomAD3 genomes
AF:
0.00121
AC:
184
AN:
152178
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000459
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000916
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000622
Gnomad FIN
AF:
0.000283
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00206
Gnomad OTH
AF:
0.00239
GnomAD3 exomes
AF:
0.00126
AC:
317
AN:
251248
Hom.:
0
AF XY:
0.00118
AC XY:
160
AN XY:
135782
show subpopulations
Gnomad AFR exome
AF:
0.000554
Gnomad AMR exome
AF:
0.000607
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000196
Gnomad FIN exome
AF:
0.000785
Gnomad NFE exome
AF:
0.00226
Gnomad OTH exome
AF:
0.00114
GnomAD4 exome
AF:
0.00164
AC:
2396
AN:
1461848
Hom.:
2
Cov.:
33
AF XY:
0.00157
AC XY:
1139
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.000299
Gnomad4 AMR exome
AF:
0.000783
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000255
Gnomad4 FIN exome
AF:
0.000936
Gnomad4 NFE exome
AF:
0.00199
Gnomad4 OTH exome
AF:
0.000977
GnomAD4 genome
AF:
0.00121
AC:
184
AN:
152296
Hom.:
0
Cov.:
33
AF XY:
0.000940
AC XY:
70
AN XY:
74466
show subpopulations
Gnomad4 AFR
AF:
0.000457
Gnomad4 AMR
AF:
0.000915
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000622
Gnomad4 FIN
AF:
0.000283
Gnomad4 NFE
AF:
0.00206
Gnomad4 OTH
AF:
0.00236
Alfa
AF:
0.00155
Hom.:
0
Bravo
AF:
0.00121
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00234
EpiControl
AF:
0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:4
Likely benign, criteria provided, single submitterclinical testingGeneDxNov 24, 2020This variant is associated with the following publications: (PMID: 30564623) -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jun 27, 2017- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenSep 01, 2022COL6A3: BP4, BP7 -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Collagen 6-related myopathy Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.68
CADD
Benign
14
DANN
Benign
0.67

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: rs148970984; hg19: chr2-238303450; COSMIC: COSV55089745; API