chr20-44720078-G-T

Position:

• chr20-44720078-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003881.4(CCN5):​c.242G>T​(p.Gly81Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCN5 NM_003881.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.12

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCN5	NM_003881.4	c.242G>T	p.Gly81Val	missense_variant	2/4	ENST00000190983.5	NP_003872.1
CCN5	NM_001323370.2	c.242G>T	p.Gly81Val	missense_variant	3/5		NP_001310299.1
CCN5	NM_001323369.2	c.242G>T	p.Gly81Val	missense_variant	2/3		NP_001310298.1
KCNK15-AS1	NR_132377.1	n.439-3285C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCN5	ENST00000190983.5	c.242G>T	p.Gly81Val	missense_variant	2/4	1	NM_003881.4	ENSP00000190983.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.03e-7 AC: 1 AN: 1422692 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 705786

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000260

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.: 33

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

Aug 06, 2024

The c.242G>T (p.G81V) alteration is located in exon 2 (coding exon 2) of the WISP2 gene. This alteration results from a G to T substitution at nucleotide position 242, causing the glycine (G) at amino acid position 81 to be replaced by a valine (V). 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	0.12
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.25	T;.;T
Eigen	Benign	-0.036
Eigen_PC	Benign	-0.055
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	.;T;T
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.7	M;M;M
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.026	D;D;D
Sift4G	Benign	0.077	T;T;T
Polyphen		0.61	P;.;P
Vest4		0.37
MutPred		0.70		Loss of disorder (P = 0.0659);Loss of disorder (P = 0.0659);Loss of disorder (P = 0.0659);
MVP		0.40
MPC		0.44
ClinPred		0.84	D
GERP RS		4.4
Varity_R		0.27
gMVP		0.27

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: rs2065887889; hg19: chr20-43348719;