chr6-56061662-C-T
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_030820.4(COL21A1):c.2192G>A(p.Gly731Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000315 in 1,587,446 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)
Exomes 𝑓: 0.0000028 ( 0 hom. )
Consequence
COL21A1
NM_030820.4 missense
NM_030820.4 missense
Scores
8
8
3
Clinical Significance
Conservation
PhyloP100: 2.51
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL21A1 | NM_030820.4 | c.2192G>A | p.Gly731Asp | missense_variant | 25/30 | ENST00000244728.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL21A1 | ENST00000244728.10 | c.2192G>A | p.Gly731Asp | missense_variant | 25/30 | 1 | NM_030820.4 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152026Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000279 AC: 4AN: 1435420Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0AN XY: 713532
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 152026Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74232
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 23, 2024 | The c.2192G>A (p.G731D) alteration is located in exon 25 (coding exon 24) of the COL21A1 gene. This alteration results from a G to A substitution at nucleotide position 2192, causing the glycine (G) at amino acid position 731 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;D;.
Sift4G
Benign
T;T;T
Polyphen
D;.;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0641);.;.;
MVP
MPC
ClinPred
D
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at