chr8-138594052-C-G

Variant names:

• chr8-138594052-C-G
• NM_152888.3:c.4580G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_152888.3(COL22A1):​c.4580G>C​(p.Gly1527Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,432,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: COL22A1 NM_152888.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.53
• Publications: 0 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: 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, 0.983

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.4580G>C	p.Gly1527Ala	missense	Exon 63 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.4580G>C	p.Gly1527Ala	missense	Exon 63 of 65	ENSP00000303153.6	Q8NFW1-1
	COL22A1	ENST00000341807.8	TSL:1	n.2265G>C		non_coding_transcript_exon	Exon 37 of 39
	COL22A1	ENST00000903590.1		c.4520G>C	p.Gly1507Ala	missense	Exon 62 of 64	ENSP00000573649.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1432692 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 713300

African (AFR) AF: 0.00 AC: 0 AN: 30718

American (AMR) AF: 0.00 AC: 0 AN: 36768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24826

East Asian (EAS) AF: 0.00 AC: 0 AN: 37754

South Asian (SAS) AF: 0.00 AC: 0 AN: 82840

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102138

Other (OTH) AF: 0.00 AC: 0 AN: 58996

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.94
Sift	Benign	0.18	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.85		Loss of catalytic residue at P1523 (P = 0.0852)
MVP		0.64
MPC		0.091
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.33
gMVP		0.76
Mutation Taster		=78/22	polymorphism

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

hg19: chr8-139606295;