Genetic Variant NM_003613.4:c.3496G>T (chr15-65196790-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003613.4(CILP):c.3496G>T(p.Gly1166Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 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. G1166S) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CILP
NM_003613.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.416

Publications

28 publications found

Variant links:

Genes affected

CILP (HGNC:1980): (cartilage intermediate layer protein) Major alterations in the composition of the cartilage extracellular matrix occur in joint disease, such as osteoarthrosis. This gene encodes the cartilage intermediate layer protein (CILP), which increases in early osteoarthrosis cartilage. The encoded protein was thought to encode a protein precursor for two different proteins; an N-terminal CILP and a C-terminal homolog of NTPPHase, however, later studies identified no nucleotide pyrophosphatase phosphodiesterase (NPP) activity. The full-length and the N-terminal domain of this protein was shown to function as an IGF-1 antagonist. An allelic variant of this gene has been associated with lumbar disc disease. [provided by RefSeq, Sep 2010]

CILP links:

ENSG00000299580 (HGNC:):

ENSG00000299580 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.086685956).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003613.4. 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
	CILP	NM_003613.4	MANE Select	c.3496G>T	p.Gly1166Cys	missense	Exon 9 of 9	NP_003604.4	O75339

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CILP	ENST00000261883.6	TSL:1 MANE Select	c.3496G>T	p.Gly1166Cys	missense	Exon 9 of 9	ENSP00000261883.4	O75339
CILP	ENST00000888802.1		c.3502G>T	p.Gly1168Cys	missense	Exon 9 of 9	ENSP00000558861.1
CILP	ENST00000941157.1		c.3496G>T	p.Gly1166Cys	missense	Exon 9 of 9	ENSP00000611216.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1442392

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715088

African (AFR)

AF:

0.00

AC:

AN:

33120

American (AMR)

AF:

0.00

AC:

AN:

42936

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24746

East Asian (EAS)

AF:

0.00

AC:

AN:

39456

South Asian (SAS)

AF:

0.00

AC:

AN:

83268

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52856

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5672

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1100868

Other (OTH)

AF:

0.00

AC:

AN:

59470

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

9.6

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.027

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.097

LIST_S2

Benign

0.26

M_CAP

Benign

0.0068

MetaRNN

Benign

0.087

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

0.42

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.64

REVEL

Benign

0.072

Sift

Benign

0.038

Sift4G

Benign

0.097

Polyphen

0.56

Vest4

0.11

MutPred

0.28

Gain of sheet (P = 0.0101)

MVP

0.36

MPC

0.15

ClinPred

0.17

GERP RS

3.5

Varity_R

0.074

gMVP

0.27

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over