8-138826669-T-C

Variant names:

• chr8-138826669-T-C
• rs2292927
• NM_152888.3:c.958A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_152888.3(COL22A1):​c.958A>G​(p.Ser320Gly) variant causes a missense change. The variant allele was found at a frequency of 0.809 in 1,612,904 control chromosomes in the GnomAD database, including 528,102 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. S320C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.82 (51177 hom., cov: 29)
  • Exomes 𝑓: 0.81 (476925 hom.)
• Consequence: COL22A1 NM_152888.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.05
• Publications: 34 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.695768E-7).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.854 is higher than 0.05.

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.958A>G	p.Ser320Gly	missense	Exon 6 of 65	NP_690848.1	Q8NFW1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL22A1	ENST00000303045.11	TSL:1 MANE Select	c.958A>G	p.Ser320Gly	missense	Exon 6 of 65	ENSP00000303153.6	Q8NFW1-1
	COL22A1	ENST00000903590.1		c.958A>G	p.Ser320Gly	missense	Exon 6 of 64	ENSP00000573649.1
	COL22A1	ENST00000903591.1		c.958A>G	p.Ser320Gly	missense	Exon 6 of 62	ENSP00000573650.1

Frequencies

GnomAD3 genomes AF: 0.820 AC: 124519 AN: 151838 Hom.: 51116 Cov.: 29

Gnomad AFR AF: 0.861

Gnomad AMI AF: 0.789

Gnomad AMR AF: 0.825

Gnomad ASJ AF: 0.778

Gnomad EAS AF: 0.743

Gnomad SAS AF: 0.870

Gnomad FIN AF: 0.791

Gnomad MID AF: 0.835

Gnomad NFE AF: 0.804

Gnomad OTH AF: 0.801

GnomAD2 exomes AF: 0.814 AC: 204483 AN: 251314 AF XY: 0.815

Gnomad AFR exome AF: 0.863

Gnomad AMR exome AF: 0.833

Gnomad ASJ exome AF: 0.782

Gnomad EAS exome AF: 0.736

Gnomad FIN exome AF: 0.792

Gnomad NFE exome AF: 0.805

Gnomad OTH exome AF: 0.811

GnomAD4 exome AF: 0.808 AC: 1179769 AN: 1460948 Hom.: 476925 Cov.: 41 AF XY: 0.809 AC XY: 587997 AN XY: 726804

African (AFR) AF: 0.864 AC: 28913 AN: 33458

American (AMR) AF: 0.830 AC: 37117 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.780 AC: 20387 AN: 26128

East Asian (EAS) AF: 0.757 AC: 30045 AN: 39686

South Asian (SAS) AF: 0.871 AC: 75078 AN: 86228

European-Finnish (FIN) AF: 0.791 AC: 42232 AN: 53404

Middle Eastern (MID) AF: 0.805 AC: 4628 AN: 5752

European-Non Finnish (NFE) AF: 0.803 AC: 892759 AN: 1111202

Other (OTH) AF: 0.805 AC: 48610 AN: 60368

GnomAD4 genome AF: 0.820 AC: 124633 AN: 151956 Hom.: 51177 Cov.: 29 AF XY: 0.820 AC XY: 60905 AN XY: 74272

African (AFR) AF: 0.862 AC: 35712 AN: 41452

American (AMR) AF: 0.825 AC: 12584 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.778 AC: 2700 AN: 3470

East Asian (EAS) AF: 0.743 AC: 3814 AN: 5134

South Asian (SAS) AF: 0.869 AC: 4161 AN: 4790

European-Finnish (FIN) AF: 0.791 AC: 8361 AN: 10566

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.804 AC: 54634 AN: 67964

Other (OTH) AF: 0.804 AC: 1699 AN: 2114

Alfa AF: 0.809 Hom.: 224737

Bravo AF: 0.822

TwinsUK AF: 0.811 AC: 3008

ALSPAC AF: 0.800 AC: 3084

ESP6500AA AF: 0.866 AC: 3816

ESP6500EA AF: 0.810 AC: 6970

ExAC AF: 0.814 AC: 98884

Asia WGS AF: 0.807 AC: 2808 AN: 3478

EpiCase AF: 0.804

EpiControl AF: 0.810

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.042
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	18
DANN	Benign	0.45
DEOGEN2	Benign	0.00040	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	5.7e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-2.9	N
PhyloP100		6.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	2.5	N
REVEL	Benign	0.097
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.12
MPC		0.077
ClinPred		0.015	T
GERP RS		5.2
Varity_R		0.059
gMVP		0.29
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2292927; hg19: chr8-139838912; COSMIC: COSV57328982;