19-19540281-C-A

Position:

• chr19-19540281-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_153221.2(CILP2):​c.241C>A​(p.Arg81Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,447,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CILP2 NM_153221.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.91

Genes affected

CILP2 (HGNC:24213): (cartilage intermediate layer protein 2) Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CILP2	NM_153221.2	c.241C>A	p.Arg81Ser	missense_variant	3/8	ENST00000291495.5	NP_694953.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CILP2	ENST00000291495.5	c.241C>A	p.Arg81Ser	missense_variant	3/8	1	NM_153221.2	ENSP00000291495.3
CILP2	ENST00000586018.5	c.259C>A	p.Arg87Ser	missense_variant	3/8	2		ENSP00000467413.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447302 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 719684

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2021

The c.241C>A (p.R81S) alteration is located in exon 3 (coding exon 3) of the CILP2 gene. This alteration results from a C to A substitution at nucleotide position 241, causing the arginine (R) at amino acid position 81 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	.;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Pathogenic	3.6	.;H
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.7	.;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0030	.;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.99	.;D
Vest4		0.90
MutPred		0.69		.;Gain of phosphorylation at Y83 (P = 0.1245);
MVP		0.58
MPC		1.2
ClinPred		1.0	D
GERP RS		3.2
Varity_R		0.74
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs747547566; hg19: chr19-19651090;