Genetic Variant CNTLN:p.Pro20Leu (chr9-17135124-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017738.4(CNTLN):c.59C>T(p.Pro20Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000436 in 1,606,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P20H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CNTLN
NM_017738.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.67

Publications

1 publications found

Variant links:

Genes affected

CNTLN (HGNC:23432): (centlein) Enables protein domain specific binding activity; protein kinase binding activity; and protein-macromolecule adaptor activity. Involved in centriole-centriole cohesion and protein localization to organelle. Located in cytosol; microtubule organizing center; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

CNTLN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.048673958).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTLN	NM_017738.4 link	c.59C>T	p.Pro20Leu	missense_variant	Exon 1 of 26	ENST00000380647.8	NP_060208.2	Q9NXG0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CNTLN	ENST00000380647.8 link	c.59C>T	p.Pro20Leu	missense_variant	Exon 1 of 26	1	NM_017738.4	ENSP00000370021.3	Q9NXG0-2
CNTLN	ENST00000380641.4 link	c.59C>T	p.Pro20Leu	missense_variant	Exon 1 of 7	2		ENSP00000370015.3	Q9NXG0-3
CNTLN	ENST00000484374.1 link	n.143C>T		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000434

AC:

AN:

230468

AF XY:

0.00000794

show subpopulations

Gnomad AFR exome

AF:

0.0000742

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1454608

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

723028

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33420

American (AMR)

AF:

0.00

AC:

AN:

43882

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25758

East Asian (EAS)

AF:

0.00

AC:

AN:

39494

South Asian (SAS)

AF:

0.00

AC:

AN:

84740

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51784

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5554

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109876

Other (OTH)

AF:

0.0000166

AC:

AN:

60100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.0000263

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41472

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2092

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

Genome Het

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

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.0046

MetaRNN

Benign

0.049

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.2

L;L

PhyloP100

1.7

PrimateAI

Uncertain

0.73

PROVEAN

Benign

0.24

N;N

REVEL

Benign

0.030

Sift

Benign

0.52

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.0010

B;B

Vest4

0.24

MutPred

0.20

Loss of glycosylation at P20 (P = 0.0321);Loss of glycosylation at P20 (P = 0.0321);

MVP

0.040

ClinPred

0.040

GERP RS

1.5

PromoterAI

0.039

Neutral

(source)

gMVP

0.11

Mutation Taster

=97/3

polymorphism

(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