chr20-44715415-C-A

Variant names:

• chr20-44715415-C-A
• rs1164479756
• NM_003881.4:c.25C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003881.4(CCN5):​c.25C>A​(p.Leu9Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CCN5 NM_003881.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.15
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2369389).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003881.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCN5	NM_003881.4	MANE Select	c.25C>A	p.Leu9Ile	missense	Exon 1 of 4	NP_003872.1	O76076-1
	CCN5	NM_001323370.2		c.25C>A	p.Leu9Ile	missense	Exon 2 of 5	NP_001310299.1	O76076-1
	CCN5	NM_001323369.2		c.25C>A	p.Leu9Ile	missense	Exon 1 of 3	NP_001310298.1	O76076-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCN5	ENST00000190983.5	TSL:1 MANE Select	c.25C>A	p.Leu9Ile	missense	Exon 1 of 4	ENSP00000190983.4	O76076-1
	CCN5	ENST00000372865.4	TSL:1	c.25C>A	p.Leu9Ile	missense	Exon 1 of 3	ENSP00000361956.4	O76076-2
	CCN5	ENST00000372868.6	TSL:3	c.25C>A	p.Leu9Ile	missense	Exon 2 of 5	ENSP00000361959.2	O76076-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451386 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 720862

African (AFR) AF: 0.00 AC: 0 AN: 33324

American (AMR) AF: 0.00 AC: 0 AN: 43364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25788

East Asian (EAS) AF: 0.00 AC: 0 AN: 39428

South Asian (SAS) AF: 0.00 AC: 0 AN: 84104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107340

Other (OTH) AF: 0.0000167 AC: 1 AN: 60008

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.1
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.43	N
REVEL	Uncertain	0.31
Sift	Benign	0.051	T
Sift4G	Benign	0.074	T
Polyphen		0.99	D
Vest4		0.35
MutPred		0.31		Loss of disorder (P = 0.0327)
MVP		0.22
MPC		0.85
ClinPred		0.88	D
GERP RS		4.0
PromoterAI		0.15	Neutral
Varity_R		0.060
gMVP		0.43
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs1164479756; hg19: chr20-43344056;