rs200710788

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001849.4(COL6A2):c.511G>A(p.Gly171Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,608,218 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G171G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 4 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:7B:4

Conservation

PhyloP100: 2.40

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.044142783).

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4 link	c.511G>A	p.Gly171Arg	missense_variant	Exon 3 of 28	ENST00000300527.9	NP_001840.3	P12110-1A0A384MDP3
COL6A2	NM_058174.3 link	c.511G>A	p.Gly171Arg	missense_variant	Exon 3 of 28		NP_478054.2	P12110-2
COL6A2	NM_058175.3 link	c.511G>A	p.Gly171Arg	missense_variant	Exon 3 of 28		NP_478055.2	P12110-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9 link	c.511G>A	p.Gly171Arg	missense_variant	Exon 3 of 28	1	NM_001849.4	ENSP00000300527.4		P12110-1

Frequencies

GnomAD3 genomes

AF:

0.00116

AC:

177

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00116

AC:

272

AN:

233566

Hom.:

AF XY:

0.00118

AC XY:

153

AN XY:

129188

show subpopulations

Gnomad AFR exome

AF:

0.000435

Gnomad AMR exome

AF:

0.000381

Gnomad ASJ exome

AF:

0.00229

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00211

Gnomad FIN exome

AF:

0.0000534

Gnomad NFE exome

AF:

0.00153

Gnomad OTH exome

AF:

0.00121

GnomAD4 exome

AF:

0.00130

AC:

1889

AN:

1455982

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

954

AN XY:

724110

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.000449

Gnomad4 ASJ exome

AF:

0.00204

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00187

Gnomad4 FIN exome

AF:

0.000120

Gnomad4 NFE exome

AF:

0.00140

Gnomad4 OTH exome

AF:

0.00126

GnomAD4 genome

AF:

0.00116

AC:

177

AN:

152236

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00131

Hom.:

Bravo

AF:

0.00112

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000833

AC:

ExAC

AF:

0.00101

AC:

121

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00229

EpiControl

AF:

0.00160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:7Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Jan 21, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously as a variant of uncertain significance in patients with clinically suspected limb-girdle muscular dystrophy; however, no further clinical or segregation information was provided (PMID: 30564623); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24036952, 34803902, 36920900, 37091313, 30564623) -

May 18, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL6A2: BS2 -

Apr 12, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1 -

COL6A2-related disorder

Uncertain:2

Feb 08, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The COL6A2 c.511G>A variant is predicted to result in the amino acid substitution p.Gly171Arg. This variant has been previously observed in a large cohort of individuals with clinically suspected limb-girdle muscular dystrophy (Table S7, Nallamilli et al. 2018. PubMed ID: 30564623). This variant is reported in 0.23% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including one homozygote (http://gnomad.broadinstitute.org/variant/21-47532288-G-A). This variant has conflicting interpretations of benign, likely benign, and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/282184/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Jul 18, 2018

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Collagen 6-related myopathy

Uncertain:1Benign:1

Dec 05, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

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

Uncertain:1Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 06, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP2, PP3, BS2 -

Tip-toe gait

Pathogenic:1

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Myopathy refers to diseases that affect skeletal Muscles. These diseases attack muscle fibers, making muscles weak. Inherited myopathies are often caused by inheriting an abnormal gene mutation from a parent that causes the disease. Symptoms of congenital myopathies usually start at birth or in early childhood, but may not appear until the teen years or even later in adulthood. Congenital myopathies are somewhat unique compared with other inherited myopathies, as weakness typically affects all muscles and is often not progressive. Symptoms are: Muscle weakness, most commonly of upper arms and shoulders and thighs, muscle cramps, stiffness and spasms, fatigue with exertion and lack of energy. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. -

Myosclerosis

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

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

0.22

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;.;T;.;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.92

D;D;D;.;D

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.044

T;T;T;T;T

MetaSVM

Uncertain

0.29

MutationAssessor

Benign

2.0

M;M;.;M;M

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-6.3

D;D;D;D;D

REVEL

Uncertain

0.59

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D;D

Polyphen

1.0

D;D;.;D;D

Vest4

0.48

MutPred

0.60

Gain of solvent accessibility (P = 0.0328);Gain of solvent accessibility (P = 0.0328);Gain of solvent accessibility (P = 0.0328);Gain of solvent accessibility (P = 0.0328);Gain of solvent accessibility (P = 0.0328);

MVP

0.93

MPC

0.51

ClinPred

0.064

GERP RS

4.3

Varity_R

0.78

gMVP

0.90

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over