rs61752496

Variant names:

• chr19-18782922-T-C
• rs61752496
• NM_000095.3:c.2267A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000095.3(COMP):​c.2267A>G​(p.Gln756Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,611,810 control chromosomes in the GnomAD database, including 1,656 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (832 hom., cov: 33)
  • Exomes 𝑓: 0.0071 (824 hom.)
• Consequence: COMP NM_000095.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.269
• Publications: 9 publications found

Genes affected

COMP (HGNC:2227): (cartilage oligomeric matrix protein) The protein encoded by this gene is a noncollagenous extracellular matrix (ECM) protein. It consists of five identical glycoprotein subunits, each with EGF-like and calcium-binding (thrombospondin-like) domains. Oligomerization results from formation of a five-stranded coiled coil and disulfides. Binding to other ECM proteins such as collagen appears to depend on divalent cations. Contraction or expansion of a 5 aa aspartate repeat and other mutations can cause pseudochondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). [provided by RefSeq, Jul 2016]

COMP Gene-Disease associations (from GenCC):

• COMP-related skeletal dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• multiple epiphyseal dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pseudoachondroplasia

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Illumina, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• multiple epiphyseal dysplasia type 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 127 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 1.78 (below the threshold of 3.09). Trascript score misZ: 1.5018 (below the threshold of 3.09). GenCC associations: The gene is linked to pseudoachondroplasia, multiple epiphyseal dysplasia type 1, multiple epiphyseal dysplasia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0025850236).
• BP6: Variant 19-18782922-T-C is Benign according to our data. Variant chr19-18782922-T-C is described in ClinVar as Benign. ClinVar VariationId is 255124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000095.3. 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
	COMP	NM_000095.3	MANE Select	c.2267A>G	p.Gln756Arg	missense	Exon 19 of 19	NP_000086.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMP	ENST00000222271.7	TSL:1 MANE Select	c.2267A>G	p.Gln756Arg	missense	Exon 19 of 19	ENSP00000222271.2	P49747-1
	COMP	ENST00000542601.6	TSL:1	c.2168A>G	p.Gln723Arg	missense	Exon 18 of 18	ENSP00000439156.2	G3XAP6
	COMP	ENST00000944187.1		c.2354A>G	p.Gln785Arg	missense	Exon 20 of 20	ENSP00000614246.1

Frequencies

GnomAD3 genomes AF: 0.0581 AC: 8830 AN: 152060 Hom.: 823 Cov.: 33

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0216

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.0378

GnomAD2 exomes AF: 0.0167 AC: 4171 AN: 249832 AF XY: 0.0131

Gnomad AFR exome AF: 0.202

Gnomad AMR exome AF: 0.00879

Gnomad ASJ exome AF: 0.0133

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000662

Gnomad OTH exome AF: 0.00866

GnomAD4 exome AF: 0.00713 AC: 10414 AN: 1459632 Hom.: 824 Cov.: 31 AF XY: 0.00667 AC XY: 4844 AN XY: 726250

African (AFR) AF: 0.213 AC: 7134 AN: 33436

American (AMR) AF: 0.0107 AC: 477 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 347 AN: 26128

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.0116 AC: 1000 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52028

Middle Eastern (MID) AF: 0.0140 AC: 72 AN: 5140

European-Non Finnish (NFE) AF: 0.000385 AC: 428 AN: 1111964

Other (OTH) AF: 0.0158 AC: 954 AN: 60302

GnomAD4 genome AF: 0.0583 AC: 8869 AN: 152178 Hom.: 832 Cov.: 33 AF XY: 0.0556 AC XY: 4138 AN XY: 74414

African (AFR) AF: 0.199 AC: 8276 AN: 41484

American (AMR) AF: 0.0214 AC: 328 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5168

South Asian (SAS) AF: 0.0143 AC: 69 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000941 AC: 64 AN: 68012

Other (OTH) AF: 0.0374 AC: 79 AN: 2112

Alfa AF: 0.0287 Hom.: 620

Bravo AF: 0.0664

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.194 AC: 854

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.0198 AC: 2404

Asia WGS AF: 0.0190 AC: 65 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Multiple epiphyseal dysplasia type 1 (1)
-	-	1	Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.9
DANN	Benign	0.72
DEOGEN2	Benign	0.29	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.98	L
PhyloP100		0.27
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.15
Sift	Benign	0.69	T
Sift4G	Benign	0.25	T
Polyphen		0.0010	B
Vest4		0.058
ClinPred		0.000017	T
GERP RS		-2.6
Varity_R		0.074
gMVP		0.40
Mutation Taster		=85/15	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: rs61752496; hg19: chr19-18893732;