15-65196790-C-T

Position:

• chr15-65196790-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.76 (44563 hom., cov: 32)
  • Exomes 𝑓: 0.81 (475925 hom.)
• Consequence: CILP NM_003613.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.416

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 3060299.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CILP	NM_003613.4	c.3496G>A	p.Gly1166Ser	missense_variant	9/9	ENST00000261883.6
CILP	XM_017022679.2	c.3424G>A	p.Gly1142Ser	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CILP	ENST00000261883.6	c.3496G>A	p.Gly1166Ser	missense_variant	9/9	1	NM_003613.4	P1

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

GnomAD3 exomes AF: 0.827 AC: 196319 AN: 237474 Hom.: 82066 AF XY: 0.831 AC XY: 106232 AN XY: 127848

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 SAS exome AF: 0.883

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

Gnomad4 AFR exome AF: 0.584

Gnomad4 AMR exome AF: 0.889

Gnomad4 ASJ exome AF: 0.825

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.887

Gnomad4 FIN exome AF: 0.779

Gnomad4 NFE exome AF: 0.803

Gnomad4 OTH exome AF: 0.812

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

Gnomad4 AFR AF: 0.592

Gnomad4 AMR AF: 0.843

Gnomad4 ASJ AF: 0.816

Gnomad4 EAS AF: 0.996

Gnomad4 SAS AF: 0.886

Gnomad4 FIN AF: 0.787

Gnomad4 NFE AF: 0.801

Gnomad4 OTH AF: 0.791

Alfa AF: 0.795 Hom.: 76305

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CILP-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	P
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

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

LitVar

Other links and lift over

dbSNP: rs938952; hg19: chr15-65489128;