20-44724974-C-A

Position:

• chr20-44724974-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003881.4(CCN5):​c.514C>A​(p.Gln172Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,432,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CCN5 NM_003881.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17527747).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCN5	NM_003881.4	c.514C>A	p.Gln172Lys	missense_variant	3/4	ENST00000190983.5	NP_003872.1
KCNK15-AS1	NR_132377.1	n.439-8181G>T		intron_variant, non_coding_transcript_variant
CCN5	NM_001323370.2	c.514C>A	p.Gln172Lys	missense_variant	4/5		NP_001310299.1
CCN5	NM_001323369.2	c.286-2113C>A		intron_variant			NP_001310298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCN5	ENST00000190983.5	c.514C>A	p.Gln172Lys	missense_variant	3/4	1	NM_003881.4	ENSP00000190983	P1
KCNK15-AS1	ENST00000445420.5	n.146+13846G>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1432930 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 709632

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.10e-7

Gnomad4 OTH exome AF: 0.00

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

Jan 26, 2023

The c.514C>A (p.Q172K) alteration is located in exon 3 (coding exon 3) of the WISP2 gene. This alteration results from a C to A substitution at nucleotide position 514, causing the glutamine (Q) at amino acid position 172 to be replaced by a lysine (K). 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	0.10
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.84
DEOGEN2	Benign	0.071	T;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.56	.;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.36	N;N
REVEL	Benign	0.19
Sift	Benign	0.84	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.42	B;B
Vest4		0.33
MutPred		0.29		Gain of ubiquitination at Q172 (P = 0.0048);Gain of ubiquitination at Q172 (P = 0.0048);
MVP		0.29
MPC		0.32
ClinPred		0.086	T
GERP RS		4.0
Varity_R		0.16
gMVP		0.55

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: rs1398468436; hg19: chr20-43353615;