15-74828074-C-G

Variant names:

• chr15-74828074-C-G
• rs750876615
• NM_001030005.3:c.205C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001030005.3(CPLX3):​c.205C>G​(p.Arg69Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R69W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CPLX3 NM_001030005.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.348
• Publications: 0 publications found

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]

ENSG00000261606 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001030005.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPLX3	NM_001030005.3	MANE Select	c.205C>G	p.Arg69Gly	missense	Exon 2 of 3	NP_001025176.1	Q8WVH0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPLX3	ENST00000395018.6	TSL:1 MANE Select	c.205C>G	p.Arg69Gly	missense	Exon 2 of 3	ENSP00000378464.4	Q8WVH0
	ENSG00000261606	ENST00000488000.6	TSL:2	n.3414C>G		non_coding_transcript_exon	Exon 13 of 14
	ENSG00000261606	ENST00000564823.1	TSL:2	n.3643C>G		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455084 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 2 AN XY: 723076

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33356

American (AMR) AF: 0.00 AC: 0 AN: 44070

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26010

East Asian (EAS) AF: 0.00 AC: 0 AN: 39478

South Asian (SAS) AF: 0.00 AC: 0 AN: 84864

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1108918

Other (OTH) AF: 0.00 AC: 0 AN: 60082

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.71	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		0.35
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.84		Gain of ubiquitination at K66 (P = 0.0248)
MVP		0.61
MPC		0.89
ClinPred		1.0	D
GERP RS		1.2
Varity_R		0.93
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs750876615; hg19: chr15-75120415;