chr21-46116677-G-A

Variant names:

• chr21-46116677-G-A
• rs878854362
• NM_001849.4:c.954G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001849.4(COL6A2):​c.954G>A​(p.Lys318Lys) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL6A2 NM_001849.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.63

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 Uncertain_significance. Variant got 4 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 rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.954G>A	p.Lys318Lys	splice_region_variant, synonymous_variant	Exon 9 of 28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.954G>A	p.Lys318Lys	splice_region_variant, synonymous_variant	Exon 9 of 28		NP_478054.2
COL6A2	NM_058175.3	c.954G>A	p.Lys318Lys	splice_region_variant, synonymous_variant	Exon 9 of 28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.954G>A	p.Lys318Lys	splice_region_variant, synonymous_variant	Exon 9 of 28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.954G>A	p.Lys318Lys	splice_region_variant, synonymous_variant	Exon 9 of 28	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.954G>A	p.Lys318Lys	splice_region_variant, synonymous_variant	Exon 8 of 27	5		ENSP00000387115.1
COL6A2	ENST00000485591.1	n.610G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Bethlem myopathy 1A Pathogenic:1

Oct 18, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.954G nucleotide in the COL6A2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 18160674, 27159402). This suggests that this nucleotide is clinically-significant, and that variants that disrupt this position are likely to be disease-causing. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with collagen VI myopathy (PMID: 20976770). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 289076). This variant is not present in population databases (ExAC no frequency). This sequence change affects codon 318 of the COL6A2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the COL6A2 protein. This variant also falls at the last nucleotide of exon 9 of the COL6A2 coding sequence, which is part of the consensus splice site for this exon. -

Collagen 6-related myopathy Pathogenic:1

Dec 23, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL6A2 c.954G>A (p.Lys318Lys) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens the canonical 5' splice donor site. At-least one study reporting a quantification of chain-specific transcript levels by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and mutation identification by sequencing of complementary DNA reported this variant as having a translational impact corresponding to the skipping of COL6A2 exon 9, namely p.Gly310_Lys318del (Brinas_2010). However, primary data supporting this outcome was not presented. The variant was absent in 250408 control chromosomes. c.954G>A has been reported in the literature as a de-novo heterozygous variant in at-least one comprehensively analyzed individual affected with a moderately progressive Collagen Type VI-Related Disorder (example, Brinas_2010). A different variant that alters the same nucleotide, namely c.954G>T has been listed in the HGMD database with a reported phenotype of Collagen VI-deficiency, supporting the relevance of this critical nucleotide. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic citing an overlapping evidence utilized in the context of this evaluation and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Uncertain:1

Jul 13, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	26
DANN	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.63		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.34		Position offset: 13
DS_DL_spliceai		0.63		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs878854362; hg19: chr21-47536591;