rs4789936

Positions:

• chr17-78901892-C-T

Variant summary

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

The NM_001243540.2(CEP295NL):​c.-64G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.488 in 644,730 control chromosomes in the GnomAD database, including 78,705 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 0.52 (20715 hom., cov: 30)
  • Exomes 𝑓: 0.48 (57990 hom.)
• Consequence: CEP295NL NM_001243540.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.23

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=-0.49).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP295NL	NM_001243540.2	c.-64G>A		5_prime_UTR_premature_start_codon_gain_variant	2/3	ENST00000322630.3	NP_001230469.1
CEP295NL	NM_001243540.2	c.-64G>A		5_prime_UTR_variant	2/3	ENST00000322630.3	NP_001230469.1
TIMP2	NM_003255.5	c.130+23067G>A		intron_variant		ENST00000262768.11	NP_003246.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP295NL	ENST00000322630.3	c.-64G>A		5_prime_UTR_premature_start_codon_gain_variant	2/3	2	NM_001243540.2	ENSP00000312767.2
CEP295NL	ENST00000322630.3	c.-64G>A		5_prime_UTR_variant	2/3	2	NM_001243540.2	ENSP00000312767.2
TIMP2	ENST00000262768.11	c.130+23067G>A		intron_variant		1	NM_003255.5	ENSP00000262768.6

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78609 AN: 151788 Hom.: 20694 Cov.: 30

Gnomad AFR AF: 0.610

Gnomad AMI AF: 0.392

Gnomad AMR AF: 0.463

Gnomad ASJ AF: 0.511

Gnomad EAS AF: 0.280

Gnomad SAS AF: 0.389

Gnomad FIN AF: 0.524

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.502

Gnomad OTH AF: 0.529

GnomAD4 exome AF: 0.479 AC: 236038 AN: 492824 Hom.: 57990 Cov.: 0 AF XY: 0.477 AC XY: 124736 AN XY: 261728

Gnomad4 AFR exome AF: 0.607

Gnomad4 AMR exome AF: 0.431

Gnomad4 ASJ exome AF: 0.511

Gnomad4 EAS exome AF: 0.299

Gnomad4 SAS exome AF: 0.404

Gnomad4 FIN exome AF: 0.509

Gnomad4 NFE exome AF: 0.502

Gnomad4 OTH exome AF: 0.491

GnomAD4 genome AF: 0.518 AC: 78678 AN: 151906 Hom.: 20715 Cov.: 30 AF XY: 0.516 AC XY: 38308 AN XY: 74270

Gnomad4 AFR AF: 0.610

Gnomad4 AMR AF: 0.462

Gnomad4 ASJ AF: 0.511

Gnomad4 EAS AF: 0.279

Gnomad4 SAS AF: 0.389

Gnomad4 FIN AF: 0.524

Gnomad4 NFE AF: 0.502

Gnomad4 OTH AF: 0.529

Alfa AF: 0.506 Hom.: 28271

Bravo AF: 0.519

Asia WGS AF: 0.334 AC: 1161 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.97
DANN	Benign	0.76

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: rs4789936; hg19: chr17-76897974; COSMIC: COSV53160740; COSMIC: COSV53160740;