21-46111490-C-T

Position:

• chr21-46111490-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001849.4(COL6A2):​c.14C>T​(p.Thr5Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0630

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15558106).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.14C>T	p.Thr5Ile	missense_variant	2/28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.14C>T	p.Thr5Ile	missense_variant	2/28		NP_478054.2
COL6A2	NM_058175.3	c.14C>T	p.Thr5Ile	missense_variant	2/28		NP_478055.2
LOC124905043	XR_007067910.1	n.542G>A		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.14C>T	p.Thr5Ile	missense_variant	2/28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.14C>T	p.Thr5Ile	missense_variant	2/28	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.14C>T	p.Thr5Ile	missense_variant	1/27	5		ENSP00000387115.1
COL6A2	ENST00000436769.5	c.14C>T	p.Thr5Ile	missense_variant	2/3	2		ENSP00000390418.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459872 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726114

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 26, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	10
DANN	Benign	0.42
DEOGEN2	Benign	0.14	T;.;T;.;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.65	T;T;T;.;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.69	N;N;.;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.27	N;N;N;N;N
REVEL	Benign	0.19
Sift	Uncertain	0.014	D;D;D;D;D
Sift4G	Benign	0.46	T;T;T;T;T
Polyphen		0.0050	B;B;.;B;B
Vest4		0.12
MutPred		0.37		Loss of disorder (P = 0.0448);Loss of disorder (P = 0.0448);Loss of disorder (P = 0.0448);Loss of disorder (P = 0.0448);Loss of disorder (P = 0.0448);
MVP		0.96
MPC		0.15
ClinPred		0.072	T
GERP RS		2.7
Varity_R		0.054
gMVP		0.29

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: rs886043160; hg19: chr21-47531404;