rs2073711

Positions:

• chr15-65201874-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_003613.4(CILP):​c.1184T>C​(p.Ile395Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.603 in 1,534,168 control chromosomes in the GnomAD database, including 285,531 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign,risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.60 (28507 hom., cov: 31)
  • Exomes 𝑓: 0.60 (257024 hom.)
• Consequence: CILP NM_003613.4 missense, splice_region
• Scores: Splicing: ADA: 0.00002264
• Clinical Significance: Benign; risk factor no assertion criteria provided B:1 O:1
• Conservation: PhyloP100: 4.12

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.767999E-5).
• BP6: Variant 15-65201874-A-G is Benign according to our data. Variant chr15-65201874-A-G is described in ClinVar as [Benign, risk_factor]. Clinvar id is 6312.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.643 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CILP	NM_003613.4	c.1184T>C	p.Ile395Thr	missense_variant, splice_region_variant	8/9	ENST00000261883.6	NP_003604.4
CILP	XM_017022679.2	c.1112T>C	p.Ile371Thr	missense_variant, splice_region_variant	7/8		XP_016878168.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CILP	ENST00000261883.6	c.1184T>C	p.Ile395Thr	missense_variant, splice_region_variant	8/9	1	NM_003613.4	ENSP00000261883.4

Frequencies

GnomAD3 genomes AF: 0.605 AC: 91854 AN: 151886 Hom.: 28480 Cov.: 31

Gnomad AFR AF: 0.650

Gnomad AMI AF: 0.635

Gnomad AMR AF: 0.601

Gnomad ASJ AF: 0.602

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.406

Gnomad FIN AF: 0.583

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.630

Gnomad OTH AF: 0.603

GnomAD3 exomes AF: 0.562 AC: 109049 AN: 193914 Hom.: 32549 AF XY: 0.559 AC XY: 58641 AN XY: 104964

Gnomad AFR exome AF: 0.645

Gnomad AMR exome AF: 0.597

Gnomad ASJ exome AF: 0.604

Gnomad EAS exome AF: 0.148

Gnomad SAS exome AF: 0.418

Gnomad FIN exome AF: 0.577

Gnomad NFE exome AF: 0.626

Gnomad OTH exome AF: 0.588

GnomAD4 exome AF: 0.603 AC: 833067 AN: 1382164 Hom.: 257024 Cov.: 44 AF XY: 0.598 AC XY: 408349 AN XY: 683040

Gnomad4 AFR exome AF: 0.638

Gnomad4 AMR exome AF: 0.601

Gnomad4 ASJ exome AF: 0.611

Gnomad4 EAS exome AF: 0.177

Gnomad4 SAS exome AF: 0.419

Gnomad4 FIN exome AF: 0.579

Gnomad4 NFE exome AF: 0.630

Gnomad4 OTH exome AF: 0.591

GnomAD4 genome AF: 0.605 AC: 91933 AN: 152004 Hom.: 28507 Cov.: 31 AF XY: 0.597 AC XY: 44329 AN XY: 74286

Gnomad4 AFR AF: 0.650

Gnomad4 AMR AF: 0.601

Gnomad4 ASJ AF: 0.602

Gnomad4 EAS AF: 0.147

Gnomad4 SAS AF: 0.408

Gnomad4 FIN AF: 0.583

Gnomad4 NFE AF: 0.630

Gnomad4 OTH AF: 0.602

Alfa AF: 0.611 Hom.: 52134

Bravo AF: 0.610

TwinsUK AF: 0.635 AC: 2354

ALSPAC AF: 0.623 AC: 2402

ESP6500AA AF: 0.636 AC: 2801

ESP6500EA AF: 0.636 AC: 5471

ExAC AF: 0.556 AC: 67413

Asia WGS AF: 0.328 AC: 1145 AN: 3476

ClinVar

Significance: Benign; risk factor

Submissions summary: Benign:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

CILP-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 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). -

Lumbar disc disease, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Benign	0.83
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.16
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.000018	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.13
Sift	Benign	0.26	T
Sift4G	Uncertain	0.034	D
Polyphen		0.0	B
Vest4		0.067
MPC		0.14
ClinPred		0.019	T
GERP RS		3.4
Varity_R		0.11
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000023
dbscSNV1_RF	Benign	0.0
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: rs2073711; hg19: chr15-65494212; COSMIC: COSV56022241;