rs373369963

chr21-46125775-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001849.4(COL6A2):c.1970-10C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000266 in 1,610,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: COL6A2 NM_001849.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002117
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -1.08

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 (BayesDel_noAF=-0.82).
• BP6: Variant 21-46125775-C-T is Benign according to our data. Variant chr21-46125775-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 288836.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.1970-10C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000300527.9
COL6A2	NM_058174.3	c.1970-10C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000397763.6
COL6A2	NM_058175.3	c.1970-10C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.1970-10C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.1970-10C>T		splice_polypyrimidine_tract_variant, intron_variant		5	NM_058174.3
COL6A2	ENST00000409416.6	c.1970-10C>T		splice_polypyrimidine_tract_variant, intron_variant		5
COL6A2	ENST00000413758.1	c.641-10C>T		splice_polypyrimidine_tract_variant, intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000230 AC: 57 AN: 247356 Hom.: 0 AF XY: 0.000208 AC XY: 28 AN XY: 134698

Gnomad AFR exome AF: 0.000251

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.000438

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000279

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000256 AC: 374 AN: 1458266 Hom.: 0 Cov.: 36 AF XY: 0.000234 AC XY: 170 AN XY: 724968

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000202

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.000530

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.000286

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.000295 AC XY: 22 AN XY: 74474

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000382 Hom.: 0

Bravo AF: 0.000351

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2021	Reported in an individual with pneumonia, neonatal respiratory distress, umbilical hernia, and hypoglycemia, who harbored a second COL6A2 variant in trans, as well as two variants in the DNAH11 gene (Wang et al., 2020); In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 31965297) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 03, 2018	- -

Collagen 6-related myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 07, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.51
Dann	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00021
dbscSNV1_RF	Benign	0.0020
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: rs373369963; hg19: chr21-47545689; COSMIC: COSV56008784;