chr20-44724789-G-T

Position:

• chr20-44724789-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003881.4(CCN5):​c.329G>T​(p.Gly110Val) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 33)
• Consequence: CCN5 NM_003881.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.74

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCN5	NM_003881.4	c.329G>T	p.Gly110Val	missense_variant	3/4	ENST00000190983.5	NP_003872.1
KCNK15-AS1	NR_132377.1	n.439-7996C>A		intron_variant, non_coding_transcript_variant
CCN5	NM_001323370.2	c.329G>T	p.Gly110Val	missense_variant	4/5		NP_001310299.1
CCN5	NM_001323369.2	c.286-2298G>T		intron_variant			NP_001310298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCN5	ENST00000190983.5	c.329G>T	p.Gly110Val	missense_variant	3/4	1	NM_003881.4	ENSP00000190983	P1
KCNK15-AS1	ENST00000445420.5	n.146+14031C>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Apr 04, 2024

The c.329G>T (p.G110V) alteration is located in exon 3 (coding exon 3) of the WISP2 gene. This alteration results from a G to T substitution at nucleotide position 329, causing the glycine (G) at amino acid position 110 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	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;T
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	3.3	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-7.9	D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.95
MutPred		0.79		Loss of disorder (P = 0.0407);Loss of disorder (P = 0.0407);
MVP		0.81
MPC		0.92
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.97
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-43353430;