chr15-65197096-G-A

Variant names:

• chr15-65197096-G-A
• rs35385195
• NM_003613.4:c.3190C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003613.4(CILP):​c.3190C>T​(p.Leu1064Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0052 in 1,614,104 control chromosomes in the GnomAD database, including 382 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (195 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (187 hom.)
• Consequence: CILP NM_003613.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.58

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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 15-65197096-G-A is Benign according to our data. Variant chr15-65197096-G-A is described in ClinVar as [Benign]. Clinvar id is 785496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0952 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CILP	NM_003613.4	c.3190C>T	p.Leu1064Leu	synonymous_variant	Exon 9 of 9	ENST00000261883.6	NP_003604.4
CILP	XM_017022679.2	c.3118C>T	p.Leu1040Leu	synonymous_variant	Exon 8 of 8		XP_016878168.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CILP	ENST00000261883.6	c.3190C>T	p.Leu1064Leu	synonymous_variant	Exon 9 of 9	1	NM_003613.4	ENSP00000261883.4

Frequencies

GnomAD3 genomes AF: 0.0277 AC: 4219 AN: 152188 Hom.: 193 Cov.: 32

Gnomad AFR AF: 0.0977

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00745

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.00723 AC: 1817 AN: 251170 AF XY: 0.00533

Gnomad AFR exome AF: 0.100

Gnomad AMR exome AF: 0.00338

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000432

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00284 AC: 4155 AN: 1461798 Hom.: 187 Cov.: 78 AF XY: 0.00235 AC XY: 1711 AN XY: 727196

Gnomad4 AFR exome AF: 0.102 AC: 3430 AN: 33480

Gnomad4 AMR exome AF: 0.00389 AC: 174 AN: 44718

Gnomad4 ASJ exome AF: 0.000115 AC: 3 AN: 26130

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39698

Gnomad4 SAS exome AF: 0.000220 AC: 19 AN: 86254

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53366

Gnomad4 NFE exome AF: 0.000154 AC: 171 AN: 1111988

Gnomad4 Remaining exome AF: 0.00545 AC: 329 AN: 60396

GnomAD4 genome AF: 0.0278 AC: 4233 AN: 152306 Hom.: 195 Cov.: 32 AF XY: 0.0265 AC XY: 1973 AN XY: 74480

Gnomad4 AFR AF: 0.0977 AC: 0.0977371 AN: 0.0977371

Gnomad4 AMR AF: 0.00745 AC: 0.00744514 AN: 0.00744514

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000621 AC: 0.000621375 AN: 0.000621375

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000309 AC: 0.000308678 AN: 0.000308678

Gnomad4 OTH AF: 0.0156 AC: 0.0156398 AN: 0.0156398

Alfa AF: 0.0137 Hom.: 37

Bravo AF: 0.0316

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 03, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.7
DANN	Benign	0.71
Mutation Taster		=96/4	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

Publications

LitVar

Other links and lift over

dbSNP: rs35385195; hg19: chr15-65489434;