Genetic Variant COL22A1:p.Ala938Asp (chr8-138688966-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_152888.3(COL22A1):c.2813C>A(p.Ala938Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,606,310 control chromosomes in the GnomAD database, including 88,596 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.31 ( 7660 hom., cov: 30)

Exomes 𝑓: 0.33 ( 80936 hom. )

Consequence

COL22A1
NM_152888.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.39

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 made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.1664968E-4).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL22A1	NM_152888.3 link	c.2813C>A	p.Ala938Asp	missense_variant	Exon 37 of 65	ENST00000303045.11	NP_690848.1	Q8NFW1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL22A1	ENST00000303045.11 link	c.2813C>A	p.Ala938Asp	missense_variant	Exon 37 of 65	1	NM_152888.3	ENSP00000303153.6		Q8NFW1-1
COL22A1	ENST00000341807.8 link	n.558C>A		non_coding_transcript_exon_variant	Exon 12 of 39	1

Frequencies

GnomAD3 genomes

AF:

0.314

AC:

47697

AN:

151712

Hom.:

7657

Cov.:

show subpopulations

Gnomad AFR

AF:

0.270

Gnomad AMI

AF:

0.300

Gnomad AMR

AF:

0.308

Gnomad ASJ

AF:

0.244

Gnomad EAS

AF:

0.202

Gnomad SAS

AF:

0.399

Gnomad FIN

AF:

0.428

Gnomad MID

AF:

0.299

Gnomad NFE

AF:

0.332

Gnomad OTH

AF:

0.311

GnomAD3 exomes

AF:

0.330

AC:

82824

AN:

251314

Hom.:

14279

AF XY:

0.333

AC XY:

45194

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.270

Gnomad AMR exome

AF:

0.342

Gnomad ASJ exome

AF:

0.236

Gnomad EAS exome

AF:

0.198

Gnomad SAS exome

AF:

0.387

Gnomad FIN exome

AF:

0.428

Gnomad NFE exome

AF:

0.331

Gnomad OTH exome

AF:

0.313

GnomAD4 exome

AF:

0.329

AC:

478620

AN:

1454478

Hom.:

80936

Cov.:

AF XY:

0.330

AC XY:

239021

AN XY:

723982

show subpopulations

Gnomad4 AFR exome

AF:

0.272

Gnomad4 AMR exome

AF:

0.336

Gnomad4 ASJ exome

AF:

0.240

Gnomad4 EAS exome

AF:

0.239

Gnomad4 SAS exome

AF:

0.387

Gnomad4 FIN exome

AF:

0.428

Gnomad4 NFE exome

AF:

0.327

Gnomad4 OTH exome

AF:

0.317

GnomAD4 genome

AF:

0.314

AC:

47730

AN:

151832

Hom.:

7660

Cov.:

AF XY:

0.321

AC XY:

23781

AN XY:

74190

show subpopulations

Gnomad4 AFR

AF:

0.270

Gnomad4 AMR

AF:

0.309

Gnomad4 ASJ

AF:

0.244

Gnomad4 EAS

AF:

0.202

Gnomad4 SAS

AF:

0.397

Gnomad4 FIN

AF:

0.428

Gnomad4 NFE

AF:

0.331

Gnomad4 OTH

AF:

0.309

Alfa

AF:

0.320

Hom.:

20249

Bravo

AF:

0.302

TwinsUK

AF:

0.335

AC:

1244

ALSPAC

AF:

0.332

AC:

1278

ESP6500AA

AF:

0.288

AC:

1269

ESP6500EA

AF:

0.328

AC:

2821

ExAC

AF:

0.329

AC:

39907

Asia WGS

AF:

0.314

AC:

1095

AN:

3478

EpiCase

AF:

0.325

EpiControl

AF:

0.324

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.76

DEOGEN2

Benign

0.0012

T;.

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.82

T;T

MetaRNN

Benign

0.00032

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.15

N;.

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.5

N;.

REVEL

Benign

0.16

Sift

Benign

0.63

T;.

Sift4G

Benign

0.21

T;T

Polyphen

0.037

B;.

Vest4

0.18

MPC

0.13

ClinPred

0.0027

GERP RS

2.7

Varity_R

0.085

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over