20-44724974-C-A

Variant names:

• chr20-44724974-C-A
• rs1398468436
• NM_003881.4:c.514C>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.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. 16/22 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
• 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=0.17527747).

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.514C>A	p.Gln172Lys	missense	Exon 3 of 4	NP_003872.1	O76076-1
	CCN5	NM_001323370.2		c.514C>A	p.Gln172Lys	missense	Exon 4 of 5	NP_001310299.1	O76076-1
	CCN5	NM_001323369.2		c.286-2113C>A		intron	N/A	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.514C>A	p.Gln172Lys	missense	Exon 3 of 4	ENSP00000190983.4	O76076-1
	CCN5	ENST00000372865.4	TSL:1	c.286-2113C>A		intron	N/A	ENSP00000361956.4	O76076-2
	CCN5	ENST00000372868.6	TSL:3	c.514C>A	p.Gln172Lys	missense	Exon 4 of 5	ENSP00000361959.2	O76076-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000141 AC: 3 AN: 212922 AF XY: 0.0000172

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000119

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000105

Gnomad OTH exome AF: 0.00

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

⚠️ 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: 32824

American (AMR) AF: 0.00 AC: 0 AN: 40878

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24654

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39048

South Asian (SAS) AF: 0.00 AC: 0 AN: 82212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4404

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1098816

Other (OTH) AF: 0.00 AC: 0 AN: 58958

⚠️ 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

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	0.10
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.84
DEOGEN2	Benign	0.071	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
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.3
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.36	N
REVEL	Benign	0.19
Sift	Benign	0.84	T
Sift4G	Benign	1.0	T
Polyphen		0.42	B
Vest4		0.33
MutPred		0.29		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
Mutation Taster		=94/6	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: rs1398468436; hg19: chr20-43353615;