8-138589291-T-G

Variant names:

• chr8-138589291-T-G
• rs1209275989
• NM_152888.3:c.4843A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_152888.3(COL22A1):​c.4843A>C​(p.Ser1615Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,644 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COL22A1 NM_152888.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.48

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL22A1	NM_152888.3	c.4843A>C	p.Ser1615Arg	missense_variant	Exon 65 of 65	ENST00000303045.11	NP_690848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL22A1	ENST00000303045.11	c.4843A>C	p.Ser1615Arg	missense_variant	Exon 65 of 65	1	NM_152888.3	ENSP00000303153.6
COL22A1	ENST00000341807.8	n.2528A>C		non_coding_transcript_exon_variant	Exon 39 of 39	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250832 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135644

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461644 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0055	T;.
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.066	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.9	N;.
REVEL	Uncertain	0.62
Sift	Uncertain	0.022	D;.
Sift4G	Uncertain	0.022	D;D
Polyphen		0.75	P;.
Vest4		0.78
MutPred		0.44		Gain of MoRF binding (P = 0.0027);.;
MVP		0.52
MPC		0.094
ClinPred		0.73	D
GERP RS		6.2
Varity_R		0.25
gMVP		0.46

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

LitVar

Other links and lift over

dbSNP: rs1209275989; hg19: chr8-139601534;