Genetic Variant NM_001243540.2:c.44+4196T>C (chr17-78897589-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001243540.2(CEP295NL):c.44+4196T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 152,138 control chromosomes in the GnomAD database, including 9,125 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 ( 9122 hom., cov: 32)

Exomes 𝑓: 0.19 ( 3 hom. )

Consequence

CEP295NL
NM_001243540.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.14

Publications

15 publications found

Variant links:

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]

CEP295NL links:

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]

TIMP2 links:

ENSG00000279339 (HGNC:):

ENSG00000279339 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 = 0.609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP295NL	NM_001243540.2 link	c.44+4196T>C		intron_variant	Intron 2 of 2	ENST00000322630.3	NP_001230469.1	Q96MC4
TIMP2	NM_003255.5 link	c.131-23670T>C		intron_variant	Intron 1 of 4	ENST00000262768.11	NP_003246.1	P16035A0A140VK57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP295NL	ENST00000322630.3 link	c.44+4196T>C		intron_variant	Intron 2 of 2	2	NM_001243540.2	ENSP00000312767.2		Q96MC4
TIMP2	ENST00000262768.11 link	c.131-23670T>C		intron_variant	Intron 1 of 4	1	NM_003255.5	ENSP00000262768.6		P16035

Frequencies

GnomAD3 genomes

AF:

0.270

AC:

41059

AN:

151954

Hom.:

9093

Cov.:

show subpopulations

Gnomad AFR

AF:

0.616

Gnomad AMI

AF:

0.0822

Gnomad AMR

AF:

0.155

Gnomad ASJ

AF:

0.142

Gnomad EAS

AF:

0.126

Gnomad SAS

AF:

0.0880

Gnomad FIN

AF:

0.122

Gnomad MID

AF:

0.259

Gnomad NFE

AF:

0.143

Gnomad OTH

AF:

0.236

GnomAD4 exome

AF:

0.188

AC:

AN:

Hom.:

Cov.:

AF XY:

0.190

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.174

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.271

AC:

41144

AN:

152074

Hom.:

9122

Cov.:

AF XY:

0.263

AC XY:

19551

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.616

AC:

25506

AN:

41434

American (AMR)

AF:

0.155

AC:

2369

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.142

AC:

494

AN:

3470

East Asian (EAS)

AF:

0.126

AC:

651

AN:

5166

South Asian (SAS)

AF:

0.0874

AC:

422

AN:

4826

European-Finnish (FIN)

AF:

0.122

AC:

1297

AN:

10594

Middle Eastern (MID)

AF:

0.259

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.143

AC:

9744

AN:

67980

Other (OTH)

AF:

0.242

AC:

510

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1179

2359

3538

4718

5897

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

360

720

1080

1440

1800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.177

Hom.:

6666

Bravo

AF:

0.289

Asia WGS

AF:

0.160

AC:

557

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

0.76

(source)

DANN

Benign

0.28

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over