chr6-56059206-C-G

Variant names:

• chr6-56059206-C-G
• rs756445035
• NM_030820.4:c.2645G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_030820.4(COL21A1):​c.2645G>C​(p.Gly882Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: COL21A1 NM_030820.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.23

Genes affected

COL21A1 (HGNC:17025): (collagen type XXI alpha 1 chain) This gene encodes the alpha chain of type XXI collagen, a member of the FACIT (fibril-associated collagens with interrupted helices) collagen family. Type XXI collagen is localized to tissues containing type I collagen and maintains the integrity of the extracellular matrix. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL21A1	NM_030820.4	c.2645G>C	p.Gly882Ala	missense_variant	Exon 29 of 30	ENST00000244728.10	NP_110447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL21A1	ENST00000244728.10	c.2645G>C	p.Gly882Ala	missense_variant	Exon 29 of 30	1	NM_030820.4	ENSP00000244728.5
COL21A1	ENST00000370819.5	c.2636G>C	p.Gly879Ala	missense_variant	Exon 28 of 29	1		ENSP00000359855.1
COL21A1	ENST00000488912.5	n.*791G>C		non_coding_transcript_exon_variant	Exon 17 of 18	1		ENSP00000433624.1
COL21A1	ENST00000488912.5	n.*791G>C		3_prime_UTR_variant	Exon 17 of 18	1		ENSP00000433624.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74334

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2645G>C (p.G882A) alteration is located in exon 29 (coding exon 28) of the COL21A1 gene. This alteration results from a G to C substitution at nucleotide position 2645, causing the glycine (G) at amino acid position 882 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D;T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	M;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.5	D;D;.
REVEL	Pathogenic	0.82
Sift	Benign	0.068	T;T;.
Sift4G	Uncertain	0.039	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.87
MutPred		0.40		Gain of MoRF binding (P = 0.1242);.;.;
MVP		0.74
MPC		0.020
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.42
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs756445035; hg19: chr6-55924004;