20-44720078-G-T

Variant names:

• chr20-44720078-G-T
• rs2065887889
• NM_003881.4:c.242G>T

Variant summary

Our verdict is Uncertain significance. The variant received 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
• 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 2 ACMG points.

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

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.242G>T	p.Gly81Val	missense	Exon 2 of 4	NP_003872.1	O76076-1
	CCN5	NM_001323370.2		c.242G>T	p.Gly81Val	missense	Exon 3 of 5	NP_001310299.1	O76076-1
	CCN5	NM_001323369.2		c.242G>T	p.Gly81Val	missense	Exon 2 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.242G>T	p.Gly81Val	missense	Exon 2 of 4	ENSP00000190983.4	O76076-1
	CCN5	ENST00000372865.4	TSL:1	c.242G>T	p.Gly81Val	missense	Exon 2 of 3	ENSP00000361956.4	O76076-2
	CCN5	ENST00000372868.6	TSL:3	c.242G>T	p.Gly81Val	missense	Exon 3 of 5	ENSP00000361959.2	O76076-1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33066

American (AMR) AF: 0.00 AC: 0 AN: 39930

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25438

East Asian (EAS) AF: 0.0000260 AC: 1 AN: 38524

South Asian (SAS) AF: 0.00 AC: 0 AN: 82832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098578

Other (OTH) AF: 0.00 AC: 0 AN: 59176

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.12
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.036
Eigen_PC	Benign	-0.055
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.1
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.026	D
Sift4G	Benign	0.077	T
Polyphen		0.61	P
Vest4		0.37
MutPred		0.70		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
Mutation Taster		=82/18	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: rs2065887889; hg19: chr20-43348719;