Genetic Variant CPLX3:p.Thr71Ala (chr15-74828080-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001030005.3(CPLX3):c.211A>G(p.Thr71Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,606,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CPLX3
NM_001030005.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.34

Variant links:

Genes affected

CPLX3 (HGNC:27652): (complexin 3) Predicted to enable SNARE binding activity. Predicted to be involved in regulation of neurotransmitter secretion and synaptic vesicle exocytosis. Predicted to be located in plasma membrane and synapse. Predicted to be part of SNARE complex. Predicted to be active in photoreceptor ribbon synapse and terminal bouton. Predicted to be anchored component of presynaptic active zone membrane and anchored component of synaptic vesicle membrane. [provided by Alliance of Genome Resources, Apr 2022]

CPLX3 links:

ENSG00000261606 (HGNC:):

ENSG00000261606 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23688558).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPLX3	NM_001030005.3 link	c.211A>G	p.Thr71Ala	missense_variant	Exon 2 of 3	ENST00000395018.6	NP_001025176.1	Q8WVH0A0A384N6F4
LOC105370897	XR_932478.1 link	n.-52A>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CPLX3	ENST00000395018.6 link	c.211A>G	p.Thr71Ala	missense_variant	Exon 2 of 3	1	NM_001030005.3	ENSP00000378464.4	Q8WVH0
ENSG00000261606	ENST00000488000.6 link	n.3420A>G		non_coding_transcript_exon_variant	Exon 13 of 14	2
ENSG00000261606	ENST00000564823.1 link	n.3649A>G		non_coding_transcript_exon_variant	Exon 5 of 6	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1454776

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722910

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:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.211A>G (p.T71A) alteration is located in exon 2 (coding exon 2) of the CPLX3 gene. This alteration results from a A to G substitution at nucleotide position 211, causing the threonine (T) at amino acid position 71 to be replaced by an alanine (A). 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

0.097

BayesDel_addAF

Benign

-0.014

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.17

Eigen

Benign

0.0085

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.56

M_CAP

Benign

0.0073

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.1

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.95

REVEL

Benign

0.12

Sift

Benign

0.37

Sift4G

Benign

0.21

Polyphen

0.27

Vest4

0.37

MutPred

0.28

Loss of phosphorylation at T71 (P = 0.0172);

MVP

0.54

MPC

0.37

ClinPred

0.69

GERP RS

4.5

Varity_R

0.20

gMVP

0.26

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