chr20-44720072-A-G

Variant names:

• chr20-44720072-A-G
• rs376593652
• NM_003881.4:c.236A>G

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.236A>G​(p.Gln79Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000281 in 1,425,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. Q79L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CCN5 NM_003881.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.10
• 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=0.25768578).

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.236A>G	p.Gln79Arg	missense	Exon 2 of 4	NP_003872.1	O76076-1
	CCN5	NM_001323370.2		c.236A>G	p.Gln79Arg	missense	Exon 3 of 5	NP_001310299.1	O76076-1
	CCN5	NM_001323369.2		c.236A>G	p.Gln79Arg	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.236A>G	p.Gln79Arg	missense	Exon 2 of 4	ENSP00000190983.4	O76076-1
	CCN5	ENST00000372865.4	TSL:1	c.236A>G	p.Gln79Arg	missense	Exon 2 of 3	ENSP00000361956.4	O76076-2
	CCN5	ENST00000372868.6	TSL:3	c.236A>G	p.Gln79Arg	missense	Exon 3 of 5	ENSP00000361959.2	O76076-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000281 AC: 4 AN: 1425130 Hom.: 0 Cov.: 31 AF XY: 0.00000283 AC XY: 2 AN XY: 707114

African (AFR) AF: 0.00 AC: 0 AN: 33112

American (AMR) AF: 0.00 AC: 0 AN: 40348

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25478

East Asian (EAS) AF: 0.00 AC: 0 AN: 38688

South Asian (SAS) AF: 0.00 AC: 0 AN: 83028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.00000364 AC: 4 AN: 1099642

Other (OTH) AF: 0.00 AC: 0 AN: 59262

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.058	T
Eigen	Benign	0.0052
Eigen_PC	Benign	0.044
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.7	L
PhyloP100		6.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.15
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.035	D
Polyphen		0.96	D
Vest4		0.15
MutPred		0.46		Gain of solvent accessibility (P = 0.1505)
MVP		0.26
MPC		0.23
ClinPred		0.91	D
GERP RS		4.4
Varity_R		0.077
gMVP		0.40
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs376593652; hg19: chr20-43348713;