dbSNP rs931304758: COL22A1:p.Gly1515Cys (chr8-138594089-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_152888.3(COL22A1):c.4543G>T(p.Gly1515Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,433,612 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. G1515S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

COL22A1
NM_152888.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.53

Publications

3 publications found

Variant links:

Genes affected

COL22A1 (HGNC:22989): (collagen type XXII alpha 1 chain) This gene encodes member of the collagen family which is thought to contribute to the stabilization of myotendinous junctions and strengthen skeletal muscle attachments during contractile activity. It belongs to the fibril-associated collagens with interrupted triple helix (FACIT) subset of the collagen superfamily, which associate with collagen fibers through their C-terminal collagenous domains and mediate protein-protein interactions through their N-terminal noncollagenous domains. The encoded protein is deposited in the basement membrane zone of the myotendinous junction which is present only at the tissue junctions of muscles, tendons, the heart, articular cartilage, and skin. A knockdown of the orthologous zebrafish gene induces a muscular dystrophy by disruption of the myotendinous junction. [provided by RefSeq, May 2017]

COL22A1 links:

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ACMG classification

Classification was made for transcript

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, 0.979

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152888.3. 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
	COL22A1	NM_152888.3	MANE Select	c.4543G>T	p.Gly1515Cys	missense	Exon 63 of 65	NP_690848.1	Q8NFW1-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL22A1	ENST00000303045.11	TSL:1 MANE Select	c.4543G>T	p.Gly1515Cys	missense	Exon 63 of 65	ENSP00000303153.6	Q8NFW1-1
COL22A1	ENST00000341807.8	TSL:1	n.2228G>T		non_coding_transcript_exon	Exon 37 of 39
COL22A1	ENST00000903590.1		c.4483G>T	p.Gly1495Cys	missense	Exon 62 of 64	ENSP00000573649.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1433612

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

713804

show subpopulations

African (AFR)

AF:

0.0000653

AC:

AN:

30606

American (AMR)

AF:

0.00

AC:

AN:

36682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24952

East Asian (EAS)

AF:

0.00

AC:

AN:

37774

South Asian (SAS)

AF:

0.00

AC:

AN:

82914

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53082

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5656

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102818

Other (OTH)

AF:

0.00

AC:

AN:

59128

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.53

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

4.7

PhyloP100

7.5

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-7.0

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MutPred

0.77

Loss of catalytic residue at P1511 (P = 0.0914)

MVP

0.62

MPC

0.089

ClinPred

1.0

GERP RS

5.9

Varity_R

0.79

gMVP

0.76

Mutation Taster

=75/25

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over