rs117725825

chr21-46132287-C-Tchr21-46132287-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001849.4(COL6A2):c.2795C>T(p.Pro932Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00345 in 1,606,806 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. P932P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0024 (3 hom., cov: 34)
  • Exomes 𝑓: 0.0036 (11 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:9 O:1
• Conservation: PhyloP100: 1.14

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.34583524).
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.2795C>T	p.Pro932Leu	missense_variant	28/28	ENST00000300527.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.2795C>T	p.Pro932Leu	missense_variant	28/28	1	NM_001849.4	P1

Frequencies

GnomAD3 genomes AF: 0.00236 AC: 359 AN: 152218 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00420

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00247 AC: 590 AN: 238806 Hom.: 1 AF XY: 0.00274 AC XY: 358 AN XY: 130830

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.00137

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00205

Gnomad FIN exome AF: 0.00167

Gnomad NFE exome AF: 0.00393

Gnomad OTH exome AF: 0.00186

GnomAD4 exome AF: 0.00357 AC: 5193 AN: 1454470 Hom.: 11 Cov.: 34 AF XY: 0.00351 AC XY: 2543 AN XY: 723836

Gnomad4 AFR exome AF: 0.000628

Gnomad4 AMR exome AF: 0.00126

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00205

Gnomad4 FIN exome AF: 0.00179

Gnomad4 NFE exome AF: 0.00421

Gnomad4 OTH exome AF: 0.00277

GnomAD4 genome AF: 0.00235 AC: 358 AN: 152336 Hom.: 3 Cov.: 34 AF XY: 0.00189 AC XY: 141 AN XY: 74486

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00419

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00372 Hom.: 0

Bravo AF: 0.00229

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00232 AC: 280

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:9 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2020	This variant is associated with the following publications: (PMID: 20981092, 20729548, 24036952, 17886299, 30564623, 30467950) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	COL6A2: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 03, 2023	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 06, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 24, 2016	- -

Bethlem myopathy 1A Benign:2

Benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -

Collagen 6-related myopathy Benign:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Bethlem myopathy 1B Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2007

- -

Ullrich congenital muscular dystrophy 1A;CN029274:Bethlem myopathy 1A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Dec 06, 2019

A heterozygous missense variation in exon 28 of the COL6A2 gene that results in the amino acid substitution of Leucine for Proline at codon 932 was detected. The observed variant has a minor allele frequency of 0.2% and 0.3% in 1000 genomes and ExAc databases respectively. The observed variation lies in the a2(VI) C2-A domain and has previously been reported in heterozygous state in a patient with Bethlem myopathy. In vitro functional studies have shown variant effect on accumulation of collagen VI in extracellular matrix (Baker et al. 2007). In summary, the variant meets our criteria to be classified as a variant of unknown significance. -

Myosclerosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

COL6A2-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 25, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.11
Cadd	Benign	16
Dann	Benign	0.66
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.8e-8	A
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.040	N
REVEL	Uncertain	0.46
Sift	Benign	0.65	T
Sift4G	Benign	0.64	T
Polyphen		0.13	B
Vest4		0.68
MVP		0.82
MPC		0.15
ClinPred		0.0098	T
GERP RS		3.2
Varity_R		0.025
gMVP		0.64

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

Other links and lift over

dbSNP: rs117725825; hg19: chr21-47552201;