Genetic Variant NM_001308173.3:c.875C>T (chr5-160253667-G-A) – 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_001308173.3(CCNJL):c.875C>T(p.Ala292Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,608,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A292G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CCNJL
NM_001308173.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.67

Publications

0 publications found

Variant links:

Genes affected

CCNJL (HGNC:25876): (cyclin J like) Predicted to enable cyclin-dependent protein serine/threonine kinase regulator activity. Predicted to be involved in mitotic cell cycle phase transition and regulation of cyclin-dependent protein serine/threonine kinase activity. Predicted to be part of cyclin-dependent protein kinase holoenzyme complex. Predicted to be active in centrosome; cytoplasm; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

CCNJL links:

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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=0.060201377).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCNJL	NM_001308173.3 link	c.875C>T	p.Ala292Val	missense_variant	Exon 6 of 6	ENST00000257536.13	NP_001295102.1	Q8IV13B4DZA8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCNJL	ENST00000257536.13 link	c.875C>T	p.Ala292Val	missense_variant	Exon 6 of 6	2	NM_001308173.3	ENSP00000257536.7		B4DZA8

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152170

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:

0.0000245

AC:

AN:

245316

AF XY:

0.0000375

show subpopulations

Gnomad AFR exome

AF:

0.000130

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:

0.00000903

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.0000124

AC:

AN:

1456472

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

723622

show subpopulations

African (AFR)

AF:

0.0000599

AC:

AN:

33398

American (AMR)

AF:

0.00

AC:

AN:

44456

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25922

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39542

South Asian (SAS)

AF:

0.0000699

AC:

AN:

85856

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52932

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00000812

AC:

AN:

1108504

Other (OTH)

AF:

0.00

AC:

AN:

60116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.613

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 08, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1019C>T (p.A340V) alteration is located in exon 7 (coding exon 6) of the CCNJL gene. This alteration results from a C to T substitution at nucleotide position 1019, causing the alanine (A) at amino acid position 340 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.0019

T;.;.;.

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.93

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.54

T;.;T;T

M_CAP

Benign

0.0066

MetaRNN

Benign

0.060

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.;.;.

PhyloP100

3.7

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.27

N;N;.;.

REVEL

Benign

0.072

Sift

Benign

0.28

T;T;.;.

Sift4G

Benign

0.57

T;T;.;T

Polyphen

0.0060

B;B;B;.

Vest4

0.026

MutPred

0.20

Loss of disorder (P = 0.0892);.;.;.;

MVP

0.12

MPC

0.25

ClinPred

0.015

GERP RS

3.2

Varity_R

0.014

gMVP

0.31

Mutation Taster

=90/10

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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NM_001308173.3:c.875C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over