rs374669775

Positions:

• chr21-46121067-C-T
• chr21-46121067-C-A

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.Arg468Ter) 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:2 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: {not_provided=1, Uncertain_significance=1, Pathogenic=2}. Variant chr21-46121067-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1402C>T	p.Arg468Ter	stop_gained	17/28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1402C>T	p.Arg468Ter	stop_gained	17/28	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3	c.1402C>T	p.Arg468Ter	stop_gained	17/28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1402C>T	p.Arg468Ter	stop_gained	17/28	1	NM_001849.4	ENSP00000300527	P1
COL6A2	ENST00000397763.6	c.1402C>T	p.Arg468Ter	stop_gained	17/28	5	NM_058174.3	ENSP00000380870
COL6A2	ENST00000409416.6	c.1402C>T	p.Arg468Ter	stop_gained	16/27	5		ENSP00000387115
COL6A2	ENST00000413758.1	c.25C>T	p.Arg9Ter	stop_gained	2/11	3		ENSP00000395751

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:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Bethlem myopathy 1A Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	Common variant that in homozygosity results in loss of function -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 01, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 565700). This premature translational stop signal has been observed in individual(s) with autosomal recessive collagenopathy (PMID: 23326386, 29419890). This variant is present in population databases (rs374669775, gnomAD 0.01%). 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). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2020

- -

Ullrich congenital muscular dystrophy 1B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 25, 2024

- -

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
MutationTaster	Benign	1.0	A;A;A;A;A
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;