21-46111479-G-A

Variant names:

• chr21-46111479-G-A
• rs2078397134
• NM_001849.4:c.3G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_001849.4(COL6A2):​c.3G>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: COL6A2 NM_001849.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.65

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]

LOC124905043 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 174 CDS bases. Genomic position: 46112037. Lost 0.057 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.3G>A	p.Met1?	start_lost	Exon 2 of 28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.3G>A	p.Met1?	start_lost	Exon 2 of 28		NP_478054.2
COL6A2	NM_058175.3	c.3G>A	p.Met1?	start_lost	Exon 2 of 28		NP_478055.2
LOC124905043	XR_007067910.1	n.553C>T		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.3G>A	p.Met1?	start_lost	Exon 2 of 28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.3G>A	p.Met1?	start_lost	Exon 2 of 28	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.3G>A	p.Met1?	start_lost	Exon 1 of 27	5		ENSP00000387115.1
COL6A2	ENST00000436769.5	c.3G>A	p.Met1?	start_lost	Exon 2 of 3	2		ENSP00000390418.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2023

This sequence change affects the initiator methionine of the COL6A2 mRNA. The next in-frame methionine is located at codon 59. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL6A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 846791). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 05, 2023

Initiation codon variant in a gene for which loss of function is a known mechanism of disease; however downstream Methionines are observed and functional data are not available to determine whether this variant is disruptive in this transcript; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24038877) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T;.;T;.;.
Eigen	Benign	0.055
Eigen_PC	Benign	0.021
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.90	D;D;D;.;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Uncertain	0.63	D
PROVEAN	Benign	-1.1	N;N;N;N;N
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.14	B;P;.;P;P
Vest4		0.77
MutPred		0.99		Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);
MVP		0.94
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.88
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2078397134; hg19: chr21-47531393;