chr21-46125782-C-A

Position:

• chr21-46125782-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001849.4(COL6A2):​c.1970-3C>A 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 0.00179 in 1,611,200 control chromosomes in the GnomAD database, including 3 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (3 hom.)
• Consequence: COL6A2 NM_001849.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9851
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:3 O:1
• Conservation: PhyloP100: 2.52

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 -3 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 174 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00204

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00101 AC: 250 AN: 248088 Hom.: 0 AF XY: 0.000867 AC XY: 117 AN XY: 134960

Gnomad AFR exome AF: 0.000564

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000516

Gnomad NFE exome AF: 0.00182

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00186 AC: 2708 AN: 1458876 Hom.: 3 Cov.: 36 AF XY: 0.00177 AC XY: 1286 AN XY: 725410

Gnomad4 AFR exome AF: 0.000419

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000844

Gnomad4 NFE exome AF: 0.00231

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00114 AC: 174 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.000926 AC XY: 69 AN XY: 74478

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00204

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00148 Hom.: 1

Bravo AF: 0.00115

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 25, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 19, 2022	Identified in two patients with Bethlem myopathy (Lampe et al., 2005; Tagliavini et al., 2014); however, functional characterization of the variant was not performed; Identified in five patients with limb-girdle muscular dystrophy type 1A who were heterozygous for this variant and did not have a second COL6A2 variant (Nallamilli et al., 2018); however, information regarding parental testing was not provided; Reported previously as a variant of uncertain significance in a patient with progressive muscle weakness in all extremities, who also had a pathogenic variant in the VCP gene and received a diagnosis of VCP myopathy (Bazrafshan et al., 2021); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 15689448, 24907562, 27656840, 30564623, 33567613) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2016	- -

Tip-toe gait Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Feb 14, 2022

Myopathy refers to diseases that affect skeletal Muscles. These diseases attack muscle fibers, making muscles weak. Inherited myopathies are often caused by inheriting an abnormal gene mutation from a parent that causes the disease. Symptoms of congenital myopathies usually start at birth or in early childhood, but may not appear until the teen years or even later in adulthood. Congenital myopathies are somewhat unique compared with other inherited myopathies, as weakness typically affects all muscles and is often not progressive. Symptoms are: Muscle weakness, most commonly of upper arms and shoulders and thighs, muscle cramps, stiffness and spasms, fatigue with exertion and lack of energy. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. -

Myosclerosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Collagen 6-related myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Ullrich congenital muscular dystrophy 1A;CN029274:Bethlem myopathy 1A Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.83
SpliceAI score (max)		0.63		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.63		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: rs201879417; hg19: chr21-47545696;