chr19-18782922-T-C

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):

• multiple epiphyseal dysplasia

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

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

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

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMP	NM_000095.3	c.2267A>G	p.Gln756Arg	missense_variant	Exon 19 of 19	ENST00000222271.7	NP_000086.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COMP	ENST00000222271.7	c.2267A>G	p.Gln756Arg	missense_variant	Exon 19 of 19	1	NM_000095.3	ENSP00000222271.2
COMP	ENST00000542601.6	c.2168A>G	p.Gln723Arg	missense_variant	Exon 18 of 18	1		ENSP00000439156.2
COMP	ENST00000425807.1	c.2108A>G	p.Gln703Arg	missense_variant	Exon 18 of 18	2		ENSP00000403792.1

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

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Dec 22, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Multiple epiphyseal dysplasia type 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

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;T;T
MetaRNN	Benign	0.0026	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.98	.;L;.
PhyloP100		0.27
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.42	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.69	T;T;T
Sift4G	Benign	0.25	T;T;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;