chr21-46125462-C-G

Position:

• chr21-46125462-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001849.4(COL6A2):​c.1817-3C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COL6A2 NM_001849.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.90

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1817-3C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1817-3C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3	c.1817-3C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1817-3C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001849.4	ENSP00000300527	P1
COL6A2	ENST00000397763.6	c.1817-3C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_058174.3	ENSP00000380870
COL6A2	ENST00000413758.1	c.485C>G	p.Pro162Arg	missense_variant	10/11	3		ENSP00000395751
COL6A2	ENST00000409416.6	c.1817-3C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000387115

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250502 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135750

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460576 Hom.: 0 Cov.: 51 AF XY: 0.00000138 AC XY: 1 AN XY: 726566

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bethlem myopathy 1A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centogene AG - the Rare Disease Company

Dec 19, 2022

This variant has previously been described in heterozygous state in a patient with Bethlem myopathy (PMID: 15689448) and in homozygous state in several patients with symptoms consistent with a COL6A2-related phenotype, at CENTOGENE. Targeted testing of the variant in two unaffected siblings of the index identified the variant in homozygous state. Therefore, the variant is reclassified to VUS. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Aug 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.0083	T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.35	T
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.21
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.12	T
MutPred		0.39		Loss of catalytic residue at P161 (P = 0.0116);
MVP		0.90
ClinPred		0.13	T
GERP RS		4.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.65		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.44		Position offset: -45
DS_AL_spliceai		0.65		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs112645828; hg19: chr21-47545376;