Genetic Variant NM_144978.3:c.13G>T (chr2-108786835-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_144978.3(CCDC138):c.13G>T(p.Val5Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,439,956 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V5L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CCDC138
NM_144978.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0630

Publications

0 publications found

Variant links:

Genes affected

CCDC138 (HGNC:26531): (coiled-coil domain containing 138)

CCDC138 links:

RANBP2 (HGNC:9848): (RAN binding protein 2) RAN is a small GTP-binding protein of the RAS superfamily that is associated with the nuclear membrane and is thought to control a variety of cellular functions through its interactions with other proteins. This gene encodes a very large RAN-binding protein that immunolocalizes to the nuclear pore complex. The protein is a giant scaffold and mosaic cyclophilin-related nucleoporin implicated in the Ran-GTPase cycle. The encoded protein directly interacts with the E2 enzyme UBC9 and strongly enhances SUMO1 transfer from UBC9 to the SUMO1 target SP100. These findings place sumoylation at the cytoplasmic filaments of the nuclear pore complex and suggest that, for some substrates, modification and nuclear import are linked events. This gene is partially duplicated in a gene cluster that lies in a hot spot for recombination on chromosome 2q. [provided by RefSeq, Jul 2008]

RANBP2 Gene-Disease associations (from GenCC):

familial acute necrotizing encephalopathy
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
Leigh syndrome
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

RANBP2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144978.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCDC138	NM_144978.3	MANE Select	c.13G>T	p.Val5Phe	missense	Exon 1 of 15	NP_659415.1	Q96M89-1
CCDC138	NM_001351544.2		c.13G>T	p.Val5Phe	missense	Exon 1 of 15	NP_001338473.1
CCDC138	NM_001351545.1		c.56G>T	p.Gly19Val	missense	Exon 1 of 14	NP_001338474.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCDC138	ENST00000295124.9	TSL:2 MANE Select	c.13G>T	p.Val5Phe	missense	Exon 1 of 15	ENSP00000295124.4	Q96M89-1
CCDC138	ENST00000412964.6	TSL:1	c.13G>T	p.Val5Phe	missense	Exon 1 of 14	ENSP00000411800.2	Q96M89-2
CCDC138	ENST00000925777.1		c.13G>T	p.Val5Phe	missense	Exon 1 of 16	ENSP00000595836.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1439956

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714280

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32554

American (AMR)

AF:

0.00

AC:

AN:

40910

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25428

East Asian (EAS)

AF:

0.00

AC:

AN:

38458

South Asian (SAS)

AF:

0.0000121

AC:

AN:

82568

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51932

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5652

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102864

Other (OTH)

AF:

0.00

AC:

AN:

59590

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Uncertain

0.047

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.025

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.80

M_CAP

Pathogenic

0.51

MetaRNN

Benign

0.25

MetaSVM

Uncertain

-0.14

MutationAssessor

Uncertain

2.0

PhyloP100

-0.063

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.41

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.022

Polyphen

0.59

Vest4

0.32

MutPred

0.17

Loss of ubiquitination at M7 (P = 0.0744)

MVP

0.86

MPC

0.23

ClinPred

0.34

GERP RS

-2.8

PromoterAI

-0.026

Neutral

(source)

Varity_R

0.11

gMVP

0.094

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.54

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.54

Position offset: -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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over