17-78901892-C-T

Variant names:

• chr17-78901892-C-T
• rs4789936
• NM_001243540.2:c.-64G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 27 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001243540.2. 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
	CEP295NL	NM_001243540.2	MANE Select	c.-64G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 3	NP_001230469.1	Q96MC4
	CEP295NL	NM_001243540.2	MANE Select	c.-64G>A		5_prime_UTR	Exon 2 of 3	NP_001230469.1	Q96MC4
	TIMP2	NM_003255.5	MANE Select	c.130+23067G>A		intron	N/A	NP_003246.1	P16035

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP295NL	ENST00000322630.3	TSL:2 MANE Select	c.-64G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 3	ENSP00000312767.2	Q96MC4
	CEP295NL	ENST00000322630.3	TSL:2 MANE Select	c.-64G>A		5_prime_UTR	Exon 2 of 3	ENSP00000312767.2	Q96MC4
	TIMP2	ENST00000262768.11	TSL:1 MANE Select	c.130+23067G>A		intron	N/A	ENSP00000262768.6	P16035

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

African (AFR) AF: 0.607 AC: 7978 AN: 13136

American (AMR) AF: 0.431 AC: 10240 AN: 23760

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 8154 AN: 15942

East Asian (EAS) AF: 0.299 AC: 9207 AN: 30792

South Asian (SAS) AF: 0.404 AC: 21954 AN: 54300

European-Finnish (FIN) AF: 0.509 AC: 23300 AN: 45792

Middle Eastern (MID) AF: 0.613 AC: 2231 AN: 3640

European-Non Finnish (NFE) AF: 0.502 AC: 139601 AN: 278234

Other (OTH) AF: 0.491 AC: 13373 AN: 27228

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

African (AFR) AF: 0.610 AC: 25274 AN: 41424

American (AMR) AF: 0.462 AC: 7056 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 1772 AN: 3466

East Asian (EAS) AF: 0.279 AC: 1439 AN: 5150

South Asian (SAS) AF: 0.389 AC: 1866 AN: 4792

European-Finnish (FIN) AF: 0.524 AC: 5539 AN: 10566

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.502 AC: 34089 AN: 67934

Other (OTH) AF: 0.529 AC: 1114 AN: 2106

Alfa AF: 0.509 Hom.: 46766

Bravo AF: 0.519

Asia WGS AF: 0.334 AC: 1161 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.97
DANN	Benign	0.76
PhyloP100		-1.2
PromoterAI		-0.019	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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