21-46126166-G-T

Variant names:

• chr21-46126166-G-T
• NM_001849.4:c.2351G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_001849.4(COL6A2):​c.2351G>T​(p.Arg784Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R784H) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40

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.

• PM1: In a domain VWFA 2 (size 190) in uniprot entity CO6A2_HUMAN there are 17 pathogenic changes around while only 5 benign (77%) in NM_001849.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-46126166-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.23464307).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.2351G>T	p.Arg784Leu	missense_variant	Exon 26 of 28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.2351G>T	p.Arg784Leu	missense_variant	Exon 26 of 28		NP_478054.2
COL6A2	NM_058175.3	c.2351G>T	p.Arg784Leu	missense_variant	Exon 26 of 28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.2351G>T	p.Arg784Leu	missense_variant	Exon 26 of 28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.2351G>T	p.Arg784Leu	missense_variant	Exon 26 of 28	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.2351G>T	p.Arg784Leu	missense_variant	Exon 25 of 27	5		ENSP00000387115.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456592 Hom.: 0 Cov.: 38 AF XY: 0.00000276 AC XY: 2 AN XY: 724792

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 07, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL6A2 c.2351G>T (p.Arg784Leu) results in a non-conservative amino acid change located in the von Willebrand factor, type A domain (IPR002035) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 246884 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2351G>T in individuals affected with Collagen Type VI-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	0.0097	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.21	T;.;.;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.88	D;D;.;D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.64	N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.43	T;T;T;T
Sift4G	Benign	0.72	T;T;T;T
Polyphen		0.039	B;B;B;B
Vest4		0.43
MutPred		0.65		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.59
MPC		0.30
ClinPred		0.47	T
GERP RS		2.8
Varity_R		0.12
gMVP		0.68

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-47546080;