rs146742517

Positions:

• chr21-46112561-G-T
• chr21-46112561-G-A

Variant summary

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

The NM_001849.4(COL6A2):​c.698G>T​(p.Arg233Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.72

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.698G>T	p.Arg233Leu	missense_variant	3/28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.698G>T	p.Arg233Leu	missense_variant	3/28	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3	c.698G>T	p.Arg233Leu	missense_variant	3/28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.698G>T	p.Arg233Leu	missense_variant	3/28	1	NM_001849.4	ENSP00000300527	P1
COL6A2	ENST00000397763.6	c.698G>T	p.Arg233Leu	missense_variant	3/28	5	NM_058174.3	ENSP00000380870
COL6A2	ENST00000409416.6	c.698G>T	p.Arg233Leu	missense_variant	2/27	5		ENSP00000387115
COL6A2	ENST00000460886.1	n.144G>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.25	T;.;.;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;D;.;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.73	D;D;D;D
MetaSVM	Uncertain	0.065	D
MutationAssessor	Uncertain	2.2	M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.5	D;D;D;D
REVEL	Pathogenic	0.72
Sift	Benign	0.15	T;D;D;D
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.83	P;P;P;D
Vest4		0.81
MutPred		0.55		Loss of ubiquitination at K236 (P = 0.0561);Loss of ubiquitination at K236 (P = 0.0561);Loss of ubiquitination at K236 (P = 0.0561);Loss of ubiquitination at K236 (P = 0.0561);
MVP		0.80
MPC		0.18
ClinPred		0.95	D
GERP RS		3.3
Varity_R		0.23
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs146742517; hg19: chr21-47532475;