Genetic Variant NM_001243540.2:c.-99+583A>G (chr17-78902551-T-C) – 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.-99+583A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.413 in 152,236 control chromosomes in the GnomAD database, including 13,163 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 0.41 ( 13145 hom., cov: 32)

Exomes 𝑓: 0.40 ( 18 hom. )

Consequence

CEP295NL
NM_001243540.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.276

Publications

7 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:

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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 = 0.441 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP295NL	NM_001243540.2 link	c.-99+583A>G		intron_variant	Intron 1 of 2	ENST00000322630.3	NP_001230469.1	Q96MC4
TIMP2	NM_003255.5 link	c.130+22408A>G		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.-99+583A>G		intron_variant	Intron 1 of 2	2	NM_001243540.2	ENSP00000312767.2		Q96MC4
TIMP2	ENST00000262768.11 link	c.130+22408A>G		intron_variant	Intron 1 of 4	1	NM_003255.5	ENSP00000262768.6		P16035

Frequencies

GnomAD3 genomes

AF:

0.413

AC:

62817

AN:

151932

Hom.:

13148

Cov.:

show subpopulations

Gnomad AFR

AF:

0.447

Gnomad AMI

AF:

0.360

Gnomad AMR

AF:

0.388

Gnomad ASJ

AF:

0.440

Gnomad EAS

AF:

0.215

Gnomad SAS

AF:

0.340

Gnomad FIN

AF:

0.473

Gnomad MID

AF:

0.471

Gnomad NFE

AF:

0.409

Gnomad OTH

AF:

0.424

GnomAD4 exome

AF:

0.398

AC:

AN:

186

Hom.:

AF XY:

0.390

AC XY:

AN XY:

136

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.400

AC:

AN:

160

Other (OTH)

AF:

0.600

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.413

AC:

62838

AN:

152050

Hom.:

13145

Cov.:

AF XY:

0.414

AC XY:

30803

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.446

AC:

18522

AN:

41498

American (AMR)

AF:

0.388

AC:

5918

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.440

AC:

1528

AN:

3470

East Asian (EAS)

AF:

0.214

AC:

1105

AN:

5166

South Asian (SAS)

AF:

0.341

AC:

1644

AN:

4824

European-Finnish (FIN)

AF:

0.473

AC:

5007

AN:

10582

Middle Eastern (MID)

AF:

0.455

AC:

133

AN:

292

European-Non Finnish (NFE)

AF:

0.409

AC:

27768

AN:

67932

Other (OTH)

AF:

0.419

AC:

885

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1906

3812

5717

7623

9529

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

594

1188

1782

2376

2970

<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:

0.416

Hom.:

5084

Bravo

AF:

0.408

Asia WGS

AF:

0.260

AC:

904

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

4.4

(source)

DANN

Benign

0.23

PhyloP100

-0.28

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over