rs1555875749

Variant names:

• chr21-46125988-G-C
• rs1555875749
• NM_001849.4:c.2173G>C

Your query was ambiguous. Multiple possible variants found:

• chr21-46125988-G-C
• chr21-46125988-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001849.4(COL6A2):​c.2173G>C​(p.Val725Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.76

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 Likely_pathogenic. Variant got 6 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.2173G>C	p.Val725Leu	missense_variant	Exon 26 of 28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.2173G>C	p.Val725Leu	missense_variant	Exon 26 of 28		NP_478054.2
COL6A2	NM_058175.3	c.2173G>C	p.Val725Leu	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.2173G>C	p.Val725Leu	missense_variant	Exon 26 of 28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.2173G>C	p.Val725Leu	missense_variant	Exon 26 of 28	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.2173G>C	p.Val725Leu	missense_variant	Exon 25 of 27	5		ENSP00000387115.1
COL6A2	ENST00000413758.1	c.*94G>C		downstream_gene_variant		3		ENSP00000395751.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 78

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;.;.;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;.;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.3	M;M;M;M
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.046	D;D;D;D
Sift4G	Uncertain	0.031	D;T;T;T
Polyphen		0.99	D;D;D;D
Vest4		0.68
MutPred		0.50		Loss of methylation at K722 (P = 0.0805);Loss of methylation at K722 (P = 0.0805);Loss of methylation at K722 (P = 0.0805);Loss of methylation at K722 (P = 0.0805);
MVP		0.95
MPC		0.60
ClinPred		0.82	D
GERP RS		4.0
Varity_R		0.52
gMVP		0.89

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: rs1555875749; hg19: chr21-47545902;