chr21-45981893-T-C

Position:

• chr21-45981893-T-C

Variant summary

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

The NM_001848.3(COL6A1):​c.43T>C​(p.Cys15Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: COL6A1 NM_001848.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.308

Genes affected

COL6A1 (HGNC:2211): (collagen type VI alpha 1 chain) The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix proteins and have a triple-helical domain as their common structural element. Collagen VI is a major structural component of microfibrils. The basic structural unit of collagen VI is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains. The alpha2(VI) and alpha3(VI) chains are encoded by the COL6A2 and COL6A3 genes, respectively. The protein encoded by this gene is the alpha 1 subunit of type VI collagen (alpha1(VI) chain). Mutations in the genes that code for the collagen VI subunits result in the autosomal dominant disorder, Bethlem myopathy. [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
COL6A1	NM_001848.3	c.43T>C	p.Cys15Arg	missense_variant	1/35	ENST00000361866.8	NP_001839.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8	c.43T>C	p.Cys15Arg	missense_variant	1/35	1	NM_001848.3	ENSP00000355180.3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 29

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

GeneDx

May 17, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Uncertain	0.62	D;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.40	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.0	D;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.0060	D;.
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.010	B;.
Vest4		0.56
MutPred		0.60		Loss of catalytic residue at W16 (P = 0.0025);Loss of catalytic residue at W16 (P = 0.0025);
MVP		0.81
MPC		0.39
ClinPred		0.67	D
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.59
gMVP		0.48

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: chr21-47401807; COSMIC: COSV62614104;