rs770842374

Positions:

chr21-46111593-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001849.4(COL6A2):c.115+2T>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,606,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

COL6A2
NM_001849.4 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 0.535

Variant links:

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]

COL6A2 links:

LOC124905043 (HGNC:):

LOC124905043 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PP5

Variant 21-46111593-T-C is Pathogenic according to our data. Variant chr21-46111593-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 476449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4 linkuse as main transcript	c.115+2T>C	splice_donor_variant, intron_variant		ENST00000300527.9	NP_001840.3	P12110-1A0A384MDP3
COL6A2	NM_058174.3 linkuse as main transcript	c.115+2T>C	splice_donor_variant, intron_variant			NP_478054.2	P12110-2
COL6A2	NM_058175.3 linkuse as main transcript	c.115+2T>C	splice_donor_variant, intron_variant			NP_478055.2	P12110-3
LOC124905043	XR_007067910.1 linkuse as main transcript	n.439A>G	non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
COL6A2	ENST00000300527.9 linkuse as main transcript	c.115+2T>C	splice_donor_variant, intron_variant	1	NM_001849.4	ENSP00000300527.4	P12110-1
COL6A2	ENST00000397763.6 linkuse as main transcript	c.115+2T>C	splice_donor_variant, intron_variant	5		ENSP00000380870.1	P12110-2
COL6A2	ENST00000409416.6 linkuse as main transcript	c.115+2T>C	splice_donor_variant, intron_variant	5		ENSP00000387115.1	P12110-3
COL6A2	ENST00000436769.5 linkuse as main transcript	c.115+2T>C	splice_donor_variant, intron_variant	2		ENSP00000390418.1	C9JH44

Frequencies

GnomAD3 genomes

AF:

0.0000200

AC:

AN:

150258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000581

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000811

AC:

AN:

246556

Hom.:

AF XY:

0.00000743

AC XY:

AN XY:

134548

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000202

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1456712

Hom.:

Cov.:

AF XY:

0.00000966

AC XY:

AN XY:

724878

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000461

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000200

AC:

AN:

150258

Hom.:

Cov.:

AF XY:

0.0000273

AC XY:

AN XY:

73276

show subpopulations

Gnomad4 AFR

AF:

0.0000246

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000581

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

ExAC

AF:

0.0000413

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Collagen 6-related myopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2019

The COL6A2 c.115+2T>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. This variant has been reported in two studies and is found in four affected individuals, including a sibling pair, one in a homozygous state and three in a compound heterozygous state. All individuals had collagen type VI spectrum disorders, two of whom were classified as moderate progressive (Brinas et al. 2010; Fraser et al. 2017). This variant is found at a frequency of 0.000294 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the evidence, the c.115+2T>C variant is classified as likely pathogenic for recessively inherited collagen type VI-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Bethlem myopathy 1A

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 17, 2023

This sequence change affects a donor splice site in intron 2 of the COL6A2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL6A2 are known to be pathogenic (PMID: 19884007, 20976770). This variant is present in population databases (rs770842374, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with autosomal recessive collagen VI myopathy (PMID: 20976770). ClinVar contains an entry for this variant (Variation ID: 476449). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2023

Published functional studies demonstrate significantly reduced COL6A2 mRNA expression (Brinas et al., 2010; Butterfield et al., 2017); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28660205, 16199547, 19884007, 20976770, 29244830) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Uncertain

0.99

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Benign

0.70

GERP RS

4.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.92

SpliceAI score (max)

0.73

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.73

Position offset: -2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over