NM_001849.4:c.1402C>T

Variant names:

• chr21-46121067-C-T
• rs374669775
• NM_001849.4:c.1402C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_001849.4(COL6A2):​c.1402C>T​(p.Arg468*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,460,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: COL6A2 NM_001849.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 O:1
• Conservation: PhyloP100: 1.04

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_pathogenic. Variant got 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 21-46121067-C-T is Pathogenic according to our data. Variant chr21-46121067-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 565700.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=3, not_provided=1}. Variant chr21-46121067-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1402C>T	p.Arg468*	stop_gained	Exon 17 of 28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1402C>T	p.Arg468*	stop_gained	Exon 17 of 28		NP_478054.2
COL6A2	NM_058175.3	c.1402C>T	p.Arg468*	stop_gained	Exon 17 of 28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1402C>T	p.Arg468*	stop_gained	Exon 17 of 28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.1402C>T	p.Arg468*	stop_gained	Exon 17 of 28	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.1402C>T	p.Arg468*	stop_gained	Exon 16 of 27	5		ENSP00000387115.1
COL6A2	ENST00000413758.1	c.25C>T	p.Arg9*	stop_gained	Exon 2 of 11	3		ENSP00000395751.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 247804 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134662

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000905

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1460480 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726550

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Bethlem myopathy 1A Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Common variant that in homozygosity results in loss of function -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg468*) in the COL6A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL6A2 are known to be pathogenic (PMID: 19884007, 20976770). This variant is present in population databases (rs374669775, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with autosomal recessive collagenopathy (PMID: 23326386, 29419890). ClinVar contains an entry for this variant (Variation ID: 565700). For these reasons, this variant has been classified as Pathogenic. -

Collagen 6-related myopathy Pathogenic:1

Feb 10, 2025

Neurogenomics Lab, Neuroscience Institute, University Of Cape Town

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM2_supporting: the highest population allele frequency in gnomAD v2.1.1 is 0.0001001 (0.01%; 1/9990 alleles in Ashkenazi Jewish population) and the variant is absent from gnomAD v3.1.2 (adequate coverage >20X confirmed). The variant is absent from an internal database. PM1 met: this variant is in the collagen triple helix (TH) repeat domain together with other pathogenic variants (PMID 24038877). PS4_moderate: variant identified in at least 5 unrelated probands with consistent phenotype for disorder (PMID 23326386, 20976770, 37569848, 29419890). PVS1 met: null variant (nonsense, predicted to undergo NMD, exon is present in a biologically-relevant transcript in a gene where LOF is a known mechanism of disease). Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/. -

not provided Pathogenic:1

Jul 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ullrich congenital muscular dystrophy 1B Uncertain:1

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Uncertain	0.41
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.40	N
Vest4		0.81
GERP RS		2.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs374669775; hg19: chr21-47540981;