NM_001243540.2:c.-64G>C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001243540.2(CEP295NL):​c.-64G>C 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 0.00000203 in 493,352 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 30)
  • Exomes 𝑓: 0.0000020 (0 hom.)
• Consequence: CEP295NL NM_001243540.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.23
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP295NL	NM_001243540.2	c.-64G>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 3	ENST00000322630.3	NP_001230469.1
CEP295NL	NM_001243540.2	c.-64G>C		5_prime_UTR_variant	Exon 2 of 3	ENST00000322630.3	NP_001230469.1
TIMP2	NM_003255.5	c.130+23067G>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.-64G>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 3	2	NM_001243540.2	ENSP00000312767.2
CEP295NL	ENST00000322630.3	c.-64G>C		5_prime_UTR_variant	Exon 2 of 3	2	NM_001243540.2	ENSP00000312767.2
TIMP2	ENST00000262768.11	c.130+23067G>C		intron_variant	Intron 1 of 4	1	NM_003255.5	ENSP00000262768.6

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000203 AC: 1 AN: 493352 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 261998

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 13150

American (AMR) AF: 0.00 AC: 0 AN: 23806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15962

East Asian (EAS) AF: 0.00 AC: 0 AN: 30814

South Asian (SAS) AF: 0.00 AC: 0 AN: 54364

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3644

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 278518

Other (OTH) AF: 0.0000367 AC: 1 AN: 27258

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.80
DANN	Benign	0.72
PhyloP100		-1.2
PromoterAI		-0.020	Neutral

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;