15-65196790-C-T

Variant names:

• chr15-65196790-C-T
• rs938952
• NM_003613.4:c.3496G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_003613.4(CILP):​c.3496G>A​(p.Gly1166Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.805 in 1,594,238 control chromosomes in the GnomAD database, including 520,488 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.76 (44563 hom., cov: 32)
  • Exomes 𝑓: 0.81 (475925 hom.)
• Consequence: CILP NM_003613.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.416
• Publications: 28 publications found

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]

ENSG00000299580 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1364165E-6).
• BP6: Variant 15-65196790-C-T is Benign according to our data. Variant chr15-65196790-C-T is described in ClinVar as Benign. ClinVar VariationId is 3060299.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

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>A	p.Gly1166Ser	missense	Exon 9 of 9	NP_003604.4	O75339

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CILP	ENST00000261883.6	TSL:1 MANE Select	c.3496G>A	p.Gly1166Ser	missense	Exon 9 of 9	ENSP00000261883.4	O75339
	CILP	ENST00000888802.1		c.3502G>A	p.Gly1168Ser	missense	Exon 9 of 9	ENSP00000558861.1
	CILP	ENST00000941157.1		c.3496G>A	p.Gly1166Ser	missense	Exon 9 of 9	ENSP00000611216.1

Frequencies

GnomAD3 genomes AF: 0.757 AC: 115106 AN: 151956 Hom.: 44525 Cov.: 32

Gnomad AFR AF: 0.592

Gnomad AMI AF: 0.910

Gnomad AMR AF: 0.843

Gnomad ASJ AF: 0.816

Gnomad EAS AF: 0.996

Gnomad SAS AF: 0.887

Gnomad FIN AF: 0.787

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.801

Gnomad OTH AF: 0.789

GnomAD2 exomes AF: 0.827 AC: 196319 AN: 237474 AF XY: 0.831

Gnomad AFR exome AF: 0.592

Gnomad AMR exome AF: 0.896

Gnomad ASJ exome AF: 0.824

Gnomad EAS exome AF: 0.997

Gnomad FIN exome AF: 0.783

Gnomad NFE exome AF: 0.807

Gnomad OTH exome AF: 0.814

GnomAD4 exome AF: 0.810 AC: 1168820 AN: 1442164 Hom.: 475925 Cov.: 64 AF XY: 0.813 AC XY: 581228 AN XY: 714944

African (AFR) AF: 0.584 AC: 19332 AN: 33112

American (AMR) AF: 0.889 AC: 38159 AN: 42916

Ashkenazi Jewish (ASJ) AF: 0.825 AC: 20412 AN: 24736

East Asian (EAS) AF: 0.999 AC: 39405 AN: 39456

South Asian (SAS) AF: 0.887 AC: 73796 AN: 83244

European-Finnish (FIN) AF: 0.779 AC: 41176 AN: 52848

Middle Eastern (MID) AF: 0.814 AC: 4617 AN: 5672

European-Non Finnish (NFE) AF: 0.803 AC: 883631 AN: 1100720

Other (OTH) AF: 0.812 AC: 48292 AN: 59460

GnomAD4 genome AF: 0.758 AC: 115202 AN: 152074 Hom.: 44563 Cov.: 32 AF XY: 0.763 AC XY: 56707 AN XY: 74342

African (AFR) AF: 0.592 AC: 24561 AN: 41460

American (AMR) AF: 0.843 AC: 12889 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.816 AC: 2833 AN: 3470

East Asian (EAS) AF: 0.996 AC: 5157 AN: 5176

South Asian (SAS) AF: 0.886 AC: 4265 AN: 4812

European-Finnish (FIN) AF: 0.787 AC: 8329 AN: 10586

Middle Eastern (MID) AF: 0.793 AC: 233 AN: 294

European-Non Finnish (NFE) AF: 0.801 AC: 54433 AN: 67958

Other (OTH) AF: 0.791 AC: 1672 AN: 2114

Alfa AF: 0.786 Hom.: 117998

Bravo AF: 0.757

TwinsUK AF: 0.799 AC: 2962

ALSPAC AF: 0.794 AC: 3060

ESP6500AA AF: 0.597 AC: 2628

ESP6500EA AF: 0.800 AC: 6879

ExAC AF: 0.821 AC: 99389

Asia WGS AF: 0.902 AC: 3134 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CILP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.4
DANN	Benign	0.44
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.42
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.70	N
REVEL	Benign	0.040
Sift	Benign	0.43	T
Sift4G	Benign	0.54	T
Polyphen		0.0	B
Vest4		0.017
MPC		0.11
ClinPred		0.00040	T
GERP RS		3.5
Varity_R		0.022
gMVP		0.26
Mutation Taster		=97/3	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: rs938952; hg19: chr15-65489128; COSMIC: COSV107244934;