6-56075504-C-A

Variant names:

• chr6-56075504-C-A
• rs1313458713
• NM_030820.4:c.1886G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_030820.4(COL21A1):​c.1886G>T​(p.Gly629Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000723 in 1,382,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G629E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: COL21A1 NM_030820.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.76
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030820.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL21A1	NM_030820.4	MANE Select	c.1886G>T	p.Gly629Val	missense	Exon 19 of 30	NP_110447.2
	COL21A1	NM_001318751.2		c.1886G>T	p.Gly629Val	missense	Exon 20 of 31	NP_001305680.1	Q96P44-1
	COL21A1	NM_001318752.2		c.1877G>T	p.Gly626Val	missense	Exon 18 of 29	NP_001305681.1	Q96P44-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL21A1	ENST00000244728.10	TSL:1 MANE Select	c.1886G>T	p.Gly629Val	missense	Exon 19 of 30	ENSP00000244728.5	Q96P44-1
	COL21A1	ENST00000370819.5	TSL:1	c.1877G>T	p.Gly626Val	missense	Exon 18 of 29	ENSP00000359855.1	Q96P44-3
	COL21A1	ENST00000488912.5	TSL:1	n.*134G>T		non_coding_transcript_exon	Exon 7 of 18	ENSP00000433624.1	H0YDH6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1382370 Hom.: 0 Cov.: 29 AF XY: 0.00000147 AC XY: 1 AN XY: 682046

African (AFR) AF: 0.00 AC: 0 AN: 29976

American (AMR) AF: 0.00 AC: 0 AN: 31964

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24544

East Asian (EAS) AF: 0.00 AC: 0 AN: 35678

South Asian (SAS) AF: 0.0000133 AC: 1 AN: 75306

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5600

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1072720

Other (OTH) AF: 0.00 AC: 0 AN: 57184

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.9	H
PhyloP100		3.8
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.90
Sift	Benign	0.34	T
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.88		Loss of catalytic residue at P625 (P = 0.1031)
MVP		0.67
MPC		0.17
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.52
gMVP		0.93
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1313458713; hg19: chr6-55940302;