8-138616915-C-T

Position:

chr8-138616915-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000303045.11(COL22A1):c.3869G>A(p.Arg1290Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

COL22A1
ENST00000303045.11 missense, splice_region

Scores

Splicing: ADA: 0.005985

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.89

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21247989).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL22A1	NM_152888.3 linkuse as main transcript	c.3869G>A	p.Arg1290Gln	missense_variant, splice_region_variant	54/65	ENST00000303045.11	NP_690848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL22A1	ENST00000303045.11 linkuse as main transcript	c.3869G>A	p.Arg1290Gln	missense_variant, splice_region_variant	54/65	1	NM_152888.3	ENSP00000303153	P1	Q8NFW1-1
COL22A1	ENST00000341807.8 linkuse as main transcript	n.1554G>A		splice_region_variant, non_coding_transcript_exon_variant	28/39	1
COL22A1	ENST00000487854.1 linkuse as main transcript	n.536G>A		non_coding_transcript_exon_variant	4/7	5

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000580

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

GnomAD3 exomes

AF:

0.0000796

AC:

AN:

251338

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000435

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461794

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Mar 17, 2023

The c.3869G>A (p.R1290Q) alteration is located in exon 54 (coding exon 53) of the COL22A1 gene. This alteration results from a G to A substitution at nucleotide position 3869, causing the arginine (R) at amino acid position 1290 to be replaced by a glutamine (Q). 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

0.087

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

T;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.049

MetaRNN

Benign

0.21

T;T

MetaSVM

Uncertain

0.50

MutationAssessor

Benign

0.86

L;.

MutationTaster

Benign

0.69

D;D

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.34

N;.

REVEL

Uncertain

0.32

Sift

Benign

0.29

T;.

Sift4G

Benign

0.16

T;T

Polyphen

1.0

D;.

Vest4

0.46

MutPred

0.39

Loss of methylation at R1290 (P = 0.0124);.;

MVP

0.56

MPC

0.097

ClinPred

0.12

GERP RS

4.3

Varity_R

0.11

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0060

dbscSNV1_RF

Benign

0.062

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over