20-44715415-C-T

Variant names:

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

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>T​(p.Leu9Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000437 in 1,603,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L9I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CCN5 NM_003881.4 missense
• Clinical Significance: Not reported in ClinVar
• 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=0.26344988).

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>T	p.Leu9Phe	missense	Exon 1 of 4	NP_003872.1	O76076-1
	CCN5	NM_001323370.2		c.25C>T	p.Leu9Phe	missense	Exon 2 of 5	NP_001310299.1	O76076-1
	CCN5	NM_001323369.2		c.25C>T	p.Leu9Phe	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>T	p.Leu9Phe	missense	Exon 1 of 4	ENSP00000190983.4	O76076-1
	CCN5	ENST00000372865.4	TSL:1	c.25C>T	p.Leu9Phe	missense	Exon 1 of 3	ENSP00000361956.4	O76076-2
	CCN5	ENST00000372868.6	TSL:3	c.25C>T	p.Leu9Phe	missense	Exon 2 of 5	ENSP00000361959.2	O76076-1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152008 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1451386 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 2 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: 0.00000361 AC: 4 AN: 1107340

Other (OTH) AF: 0.00 AC: 0 AN: 60008

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152008 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74248

African (AFR) AF: 0.00 AC: 0 AN: 41382

American (AMR) AF: 0.000196 AC: 3 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.051
Eigen_PC	Benign	-0.023
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.1
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.98	N
REVEL	Uncertain	0.31
Sift	Benign	0.040	D
Sift4G	Benign	0.14	T
Polyphen		0.90	P
Vest4		0.51
MutPred		0.28		Gain of catalytic residue at L9 (P = 0.0915)
MVP		0.33
MPC		0.85
ClinPred		0.88	D
GERP RS		4.0
PromoterAI		0.24	Neutral
Varity_R		0.061
gMVP		0.57
Mutation Taster		=61/39	polymorphism

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

Other links and lift over

dbSNP: rs1164479756; hg19: chr20-43344056;