20-44724965-C-T

Position:

• chr20-44724965-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003881.4(CCN5):​c.505C>T​(p.Leu169=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000814 in 1,593,820 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00054 (3 hom.)
• Consequence: CCN5 NM_003881.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.67

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 20-44724965-C-T is Benign according to our data. Variant chr20-44724965-C-T is described in ClinVar as [Benign]. Clinvar id is 717864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.67 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCN5	NM_003881.4	c.505C>T	p.Leu169=	synonymous_variant	3/4	ENST00000190983.5	NP_003872.1
KCNK15-AS1	NR_132377.1	n.439-8172G>A		intron_variant, non_coding_transcript_variant
CCN5	NM_001323370.2	c.505C>T	p.Leu169=	synonymous_variant	4/5		NP_001310299.1
CCN5	NM_001323369.2	c.286-2122C>T		intron_variant			NP_001310298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCN5	ENST00000190983.5	c.505C>T	p.Leu169=	synonymous_variant	3/4	1	NM_003881.4	ENSP00000190983	P1
KCNK15-AS1	ENST00000445420.5	n.146+13855G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00344 AC: 523 AN: 152170 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00108 AC: 239 AN: 221312 Hom.: 0 AF XY: 0.00104 AC XY: 126 AN XY: 120680

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.000540

Gnomad ASJ exome AF: 0.00526

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000364

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000315

Gnomad OTH exome AF: 0.000942

GnomAD4 exome AF: 0.000538 AC: 775 AN: 1441532 Hom.: 3 Cov.: 31 AF XY: 0.000501 AC XY: 358 AN XY: 714742

Gnomad4 AFR exome AF: 0.0119

Gnomad4 AMR exome AF: 0.000498

Gnomad4 ASJ exome AF: 0.00507

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000240

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000123

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00343 AC: 523 AN: 152288 Hom.: 2 Cov.: 33 AF XY: 0.00328 AC XY: 244 AN XY: 74454

Gnomad4 AFR AF: 0.0114

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00226 Hom.: 1

Bravo AF: 0.00382

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 25, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.5
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs150758194; hg19: chr20-43353606;