20-44715440-T-C

Variant names:

• chr20-44715440-T-C
• rs1198047016
• NM_003881.4:c.50T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003881.4(CCN5):​c.50T>C​(p.Leu17Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCN5 NM_003881.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.72

Genes affected

CCN5 (HGNC:12770): (cellular communication network factor 5) This gene encodes a member of the WNT1 inducible signaling pathway (WISP) protein subfamily, which belongs to the connective tissue growth factor (CTGF) family. WNT1 is a member of a family of cysteine-rich, glycosylated signaling proteins that mediate diverse developmental processes. The CTGF family members are characterized by four conserved cysteine-rich domains: insulin-like growth factor-binding domain, von Willebrand factor type C module, thrombospondin domain and C-terminal cystine knot-like (CT) domain. The encoded protein lacks the CT domain which is implicated in dimerization and heparin binding. It is 72% identical to the mouse protein at the amino acid level. This gene may be downstream in the WNT1 signaling pathway that is relevant to malignant transformation. Its expression in colon tumors is reduced while the other two WISP members are overexpressed in colon tumors. It is expressed at high levels in bone tissue, and may play an important role in modulating bone turnover. [provided by RefSeq, Jul 2008]

KCNK15-AS1 (HGNC:49901): (KCNK15 and WISP2 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.756

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCN5	NM_003881.4	c.50T>C	p.Leu17Pro	missense_variant	Exon 1 of 4	ENST00000190983.5	NP_003872.1
CCN5	NM_001323370.2	c.50T>C	p.Leu17Pro	missense_variant	Exon 2 of 5		NP_001310299.1
CCN5	NM_001323369.2	c.50T>C	p.Leu17Pro	missense_variant	Exon 1 of 3		NP_001310298.1
KCNK15-AS1	NR_132377.1	n.607+1185A>G		intron_variant	Intron 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCN5	ENST00000190983.5	c.50T>C	p.Leu17Pro	missense_variant	Exon 1 of 4	1	NM_003881.4	ENSP00000190983.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1444050 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 716490

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000333 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.50T>C (p.L17P) alteration is located in exon 1 (coding exon 1) of the WISP2 gene. This alteration results from a T to C substitution at nucleotide position 50, causing the leucine (L) at amino acid position 17 to be replaced by a proline (P). 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	Benign	0.22
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.11	T;.;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.64	.;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Uncertain	0.0077	D
MutationAssessor	Uncertain	2.1	M;M;M
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.5	N;N;N
REVEL	Uncertain	0.62
Sift	Uncertain	0.017	D;D;D
Sift4G	Uncertain	0.049	D;D;D
Polyphen		0.98	D;.;D
Vest4		0.79
MutPred		0.67		Gain of disorder (P = 0.0106);Gain of disorder (P = 0.0106);Gain of disorder (P = 0.0106);
MVP		0.69
MPC		0.91
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.73
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1198047016; hg19: chr20-43344081;