rs2376999

Variant names:

• chr17-78894782-A-G
• rs2376999
• NM_001243540.2:c.45-2323T>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001243540.2(CEP295NL):​c.45-2323T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 152,004 control chromosomes in the GnomAD database, including 9,578 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.27 (9578 hom., cov: 32)
• Consequence: CEP295NL NM_001243540.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.314

Genes affected

CEP295NL (HGNC:44659): (CEP295 N-terminal like) Predicted to enable microtubule binding activity. Predicted to be involved in regulation of centriole replication. Predicted to be located in motile cilium. Predicted to be active in centriole; centrosome; and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

TIMP2 (HGNC:11821): (TIMP metallopeptidase inhibitor 2) This gene is a member of the TIMP gene family. The proteins encoded by this gene family are natural inhibitors of the matrix metalloproteinases, a group of peptidases involved in degradation of the extracellular matrix. In addition to an inhibitory role against metalloproteinases, the encoded protein has a unique role among TIMP family members in its ability to directly suppress the proliferation of endothelial cells. As a result, the encoded protein may be critical to the maintenance of tissue homeostasis by suppressing the proliferation of quiescent tissues in response to angiogenic factors, and by inhibiting protease activity in tissues undergoing remodelling of the extracellular matrix. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.629 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP295NL	NM_001243540.2	c.45-2323T>C		intron_variant	Intron 2 of 2	ENST00000322630.3	NP_001230469.1
TIMP2	NM_003255.5	c.131-20863T>C		intron_variant	Intron 1 of 4	ENST00000262768.11	NP_003246.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP295NL	ENST00000322630.3	c.45-2323T>C		intron_variant	Intron 2 of 2	2	NM_001243540.2	ENSP00000312767.2
TIMP2	ENST00000262768.11	c.131-20863T>C		intron_variant	Intron 1 of 4	1	NM_003255.5	ENSP00000262768.6

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41373 AN: 151888 Hom.: 9546 Cov.: 32

Gnomad AFR AF: 0.635

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.271

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.235

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.273 AC: 41457 AN: 152004 Hom.: 9578 Cov.: 32 AF XY: 0.271 AC XY: 20132 AN XY: 74314

Gnomad4 AFR AF: 0.635

Gnomad4 AMR AF: 0.157

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.272

Gnomad4 SAS AF: 0.240

Gnomad4 FIN AF: 0.125

Gnomad4 NFE AF: 0.115

Gnomad4 OTH AF: 0.242

Alfa AF: 0.136 Hom.: 4115

Bravo AF: 0.290

Asia WGS AF: 0.298 AC: 1043 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	3.6
DANN	Benign	0.35

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: rs2376999; hg19: chr17-76890864;