15-65197350-T-C

Position:

• chr15-65197350-T-C

Variant summary

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

The NM_003613.4(CILP):​c.2936A>G​(p.Gln979Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.998 in 1,614,202 control chromosomes in the GnomAD database, including 803,869 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 (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.99 (74530 hom., cov: 33)
  • Exomes 𝑓: 1.0 (729339 hom.)
• Consequence: CILP NM_003613.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.880

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=6.0715035E-7).
• BP6: Variant 15-65197350-T-C is Benign according to our data. Variant chr15-65197350-T-C is described in ClinVar as [Benign]. Clinvar id is 3058903.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CILP	NM_003613.4	c.2936A>G	p.Gln979Arg	missense_variant	9/9	ENST00000261883.6	NP_003604.4
CILP	XM_017022679.2	c.2864A>G	p.Gln955Arg	missense_variant	8/8		XP_016878168.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CILP	ENST00000261883.6	c.2936A>G	p.Gln979Arg	missense_variant	9/9	1	NM_003613.4	ENSP00000261883.4

Frequencies

GnomAD3 genomes AF: 0.989 AC: 150552 AN: 152214 Hom.: 74471 Cov.: 33

Gnomad AFR AF: 0.962

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.997

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.993

GnomAD3 exomes AF: 0.997 AC: 250753 AN: 251466 Hom.: 125030 AF XY: 0.998 AC XY: 135630 AN XY: 135900

Gnomad AFR exome AF: 0.961

Gnomad AMR exome AF: 0.998

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.998

GnomAD4 exome AF: 0.999 AC: 1460241 AN: 1461870 Hom.: 729339 Cov.: 82 AF XY: 0.999 AC XY: 726565 AN XY: 727236

Gnomad4 AFR exome AF: 0.960

Gnomad4 AMR exome AF: 0.998

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.998

GnomAD4 genome AF: 0.989 AC: 150670 AN: 152332 Hom.: 74530 Cov.: 33 AF XY: 0.990 AC XY: 73722 AN XY: 74490

Gnomad4 AFR AF: 0.962

Gnomad4 AMR AF: 0.997

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.993

Alfa AF: 0.998 Hom.: 137338

Bravo AF: 0.988

TwinsUK AF: 1.00 AC: 3707

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.959 AC: 4225

ESP6500EA AF: 1.00 AC: 8596

ExAC AF: 0.997 AC: 120993

Asia WGS AF: 0.999 AC: 3473 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

Significance: Benign

Submissions summary: Benign: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

Jan 02, 2020

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	0.059
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.11
DANN	Benign	0.26
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.028	T
MetaRNN	Benign	6.1e-7	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.90	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.045
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.014
MPC		0.12
ClinPred		0.0053	T
GERP RS		-8.8
Varity_R		0.046
gMVP		0.30

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: rs2679117; hg19: chr15-65489688;