rs141166141

chr21-46122138-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001849.4(COL6A2):c.1552C>T(p.Pro518Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,612,736 control chromosomes in the GnomAD database, including 181 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P518R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0095 (9 hom., cov: 32)
  • Exomes 𝑓: 0.014 (172 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 3.58

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01017496).
• BP6: Variant 21-46122138-C-T is Benign according to our data. Variant chr21-46122138-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 93911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46122138-C-T is described in Lovd as [Benign]. Variant chr21-46122138-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00947 (1442/152288) while in subpopulation NFE AF= 0.0159 (1080/68020). AF 95% confidence interval is 0.0151. There are 9 homozygotes in gnomad4. There are 654 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.1552C>T	p.Pro518Ser	missense_variant	19/28	ENST00000300527.9
COL6A2	NM_058174.3	c.1552C>T	p.Pro518Ser	missense_variant	19/28	ENST00000397763.6
COL6A2	NM_058175.3	c.1552C>T	p.Pro518Ser	missense_variant	19/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.1552C>T	p.Pro518Ser	missense_variant	19/28	1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.1552C>T	p.Pro518Ser	missense_variant	19/28	5	NM_058174.3
COL6A2	ENST00000409416.6	c.1552C>T	p.Pro518Ser	missense_variant	18/27	5
COL6A2	ENST00000413758.1	c.175C>T	p.Pro59Ser	missense_variant	4/11	3

Frequencies

GnomAD3 genomes AF: 0.00948 AC: 1442 AN: 152170 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00294

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00903

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00508

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00882 AC: 2196 AN: 248978 Hom.: 18 AF XY: 0.00888 AC XY: 1201 AN XY: 135256

Gnomad AFR exome AF: 0.00212

Gnomad AMR exome AF: 0.00550

Gnomad ASJ exome AF: 0.00671

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00453

Gnomad NFE exome AF: 0.0155

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.0136 AC: 19920 AN: 1460448 Hom.: 172 Cov.: 33 AF XY: 0.0133 AC XY: 9638 AN XY: 726498

Gnomad4 AFR exome AF: 0.00218

Gnomad4 AMR exome AF: 0.00620

Gnomad4 ASJ exome AF: 0.00712

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000301

Gnomad4 FIN exome AF: 0.00597

Gnomad4 NFE exome AF: 0.0165

Gnomad4 OTH exome AF: 0.0123

GnomAD4 genome AF: 0.00947 AC: 1442 AN: 152288 Hom.: 9 Cov.: 32 AF XY: 0.00878 AC XY: 654 AN XY: 74464

Gnomad4 AFR AF: 0.00294

Gnomad4 AMR AF: 0.00902

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00508

Gnomad4 NFE AF: 0.0159

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0135 Hom.: 16

Bravo AF: 0.00993

TwinsUK AF: 0.0159 AC: 59

ALSPAC AF: 0.0158 AC: 61

ESP6500AA AF: 0.00387 AC: 17

ESP6500EA AF: 0.0156 AC: 134

ExAC AF: 0.00879 AC: 1064

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0140

EpiControl AF: 0.0129

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 16, 2012	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 26, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Myosclerosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Collagen 6-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	0.16
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.080
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D;.;.;.;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;.;D;D
MetaRNN	Benign	0.010	T;T;T;T;T
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	2.9	M;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0090	D;D;D;D;T
Sift4G	Benign	0.067	T;T;T;T;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.63
MVP		0.99
MPC		0.27
ClinPred		0.024	T
GERP RS		4.5
Varity_R		0.31
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs141166141; hg19: chr21-47542052;