21-46112407-G-C

Variant names:

• chr21-46112407-G-C
• rs374504636
• NM_001849.4:c.544G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001849.4(COL6A2):​c.544G>C​(p.Glu182Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.81

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2906357).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.544G>C	p.Glu182Gln	missense_variant	Exon 3 of 28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.544G>C	p.Glu182Gln	missense_variant	Exon 3 of 28		NP_478054.2
COL6A2	NM_058175.3	c.544G>C	p.Glu182Gln	missense_variant	Exon 3 of 28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.544G>C	p.Glu182Gln	missense_variant	Exon 3 of 28	1	NM_001849.4	ENSP00000300527.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456316 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 724604

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

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	Benign	0.16
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.;.;.
Eigen	Benign	-0.040
Eigen_PC	Benign	0.082
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.29	T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.93	L;L;L;L
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.45	N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.23	T;T;T;T
Sift4G	Benign	0.48	T;T;T;T
Polyphen		0.55	P;B;B;D
Vest4		0.36
MutPred		0.32		Gain of MoRF binding (P = 0.0362);Gain of MoRF binding (P = 0.0362);Gain of MoRF binding (P = 0.0362);Gain of MoRF binding (P = 0.0362);
MVP		0.89
MPC		0.19
ClinPred		0.96	D
GERP RS		4.3
Varity_R		0.15
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: rs374504636; hg19: chr21-47532321;