NM_003881.4:c.113G>T

Variant names:

• chr20-44719949-G-T
• rs142450134
• NM_003881.4:c.113G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003881.4(CCN5):​c.113G>T​(p.Arg38Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,492 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CCN5 NM_003881.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.36

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCN5	NM_003881.4	c.113G>T	p.Arg38Leu	missense_variant	Exon 2 of 4	ENST00000190983.5	NP_003872.1
CCN5	NM_001323370.2	c.113G>T	p.Arg38Leu	missense_variant	Exon 3 of 5		NP_001310299.1
CCN5	NM_001323369.2	c.113G>T	p.Arg38Leu	missense_variant	Exon 2 of 3		NP_001310298.1
KCNK15-AS1	NR_132377.1	n.439-3156C>A		intron_variant	Intron 3 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCN5	ENST00000190983.5	c.113G>T	p.Arg38Leu	missense_variant	Exon 2 of 4	1	NM_003881.4	ENSP00000190983.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461492 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727058

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T;.;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.82	.;T;T
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.8	L;L;L
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Benign	0.29
Sift	Benign	0.13	T;D;T
Sift4G	Uncertain	0.031	D;D;D
Polyphen		0.98	D;.;D
Vest4		0.47
MutPred		0.56		Loss of disorder (P = 0.076);Loss of disorder (P = 0.076);Loss of disorder (P = 0.076);
MVP		0.45
MPC		0.69
ClinPred		0.86	D
GERP RS		1.3
Varity_R		0.10
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs142450134; hg19: chr20-43348590;