Variant chr18-59318440-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_181654.4(CPLX4):c.23T>A(p.Met8Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,610,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CPLX4
NM_181654.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.68

Variant links:

Genes affected

CPLX4 (HGNC:24330): (complexin 4) This gene likely encodes a member of the complexin family. The encoded protein may be involved in synaptic vesicle exocytosis. [provided by RefSeq, Jan 2009]

CPLX4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.808

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPLX4	NM_181654.4 linkuse as main transcript	c.23T>A	p.Met8Lys	missense_variant	1/3	ENST00000299721.3	NP_857637.1	Q7Z7G2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPLX4	ENST00000299721.3 linkuse as main transcript	c.23T>A	p.Met8Lys	missense_variant	1/3	1	NM_181654.4	ENSP00000299721.3		Q7Z7G2
CPLX4	ENST00000587244.5 linkuse as main transcript	c.23T>A	p.Met8Lys	missense_variant	1/3	1		ENSP00000466304.1		K7EM04

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1458792

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725574

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000843

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2024

The c.23T>A (p.M8K) alteration is located in exon 1 (coding exon 1) of the CPLX4 gene. This alteration results from a T to A substitution at nucleotide position 23, causing the methionine (M) at amino acid position 8 to be replaced by a lysine (K). 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

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

T;D

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.021

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Uncertain

-0.11

MutationAssessor

Uncertain

2.3

.;M

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.1

.;D

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0010

.;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.97

.;D

Vest4

0.90

MutPred

0.64

Loss of ubiquitination at K6 (P = 0.0285);Loss of ubiquitination at K6 (P = 0.0285);

MVP

0.54

MPC

0.34

ClinPred

0.99

GERP RS

5.4

Varity_R

0.83

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over