19-45216125-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_001382422.1(EXOC3L2):c.2068C>G(p.Pro690Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000297 in 1,613,868 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000028 ( 1 hom. )
Consequence
EXOC3L2
NM_001382422.1 missense
NM_001382422.1 missense
Scores
5
9
Clinical Significance
Conservation
PhyloP100: 5.20
Genes affected
EXOC3L2 (HGNC:30162): (exocyst complex component 3 like 2) The protein encoded by this gene is upregulated by vascular endothelial growth factor A and interacts with exocyst complex component 4. The encoded protein may be part of an exocyst complex that plays a role in cell membrane dynamics. Mutations in this gene may be associated with Alzheimer's disease. [provided by RefSeq, May 2017]
MARK4 (HGNC:13538): (microtubule affinity regulating kinase 4) This gene encodes a member of the microtubule affinity-regulating kinase family. These protein kinases phosphorylate microtubule-associated proteins and regulate the transition between stable and dynamic microtubules. The encoded protein is associated with the centrosome throughout mitosis and may be involved in cell cycle control. Expression of this gene is a potential marker for cancer, and the encoded protein may also play a role in Alzheimer's disease. Pseudogenes of this gene are located on both the short and long arm of chromosome 3. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]
BLOC1S3 (HGNC:20914): (biogenesis of lysosomal organelles complex 1 subunit 3) This gene encodes a protein that is a component of the BLOC1 multi-subunit protein complex. This complex is necessary for the biogenesis of specialized organelles of the endosomal-lysosomal system, including platelet dense granules and melanosomes. Mutations in this gene cause Hermansky-Pudlak syndrome 8, a disease characterized by lysosomal storage defects, bleeding due to platelet storage pool deficiency, and oculocutaneous albinism. [provided by RefSeq, Jul 2008]
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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=0.14124036).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EXOC3L2 | NM_001382422.1 | c.2068C>G | p.Pro690Ala | missense_variant | 11/12 | ENST00000413988.3 | |
BLOC1S3 | XR_007066811.1 | n.1527-551G>C | intron_variant, non_coding_transcript_variant | ||||
BLOC1S3 | XR_007066813.1 | n.1499-551G>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EXOC3L2 | ENST00000413988.3 | c.2068C>G | p.Pro690Ala | missense_variant | 11/12 | 5 | NM_001382422.1 | P1 | |
MARK4 | ENST00000587566.5 | c.-276-42864G>C | intron_variant | 5 | |||||
BLOC1S3 | ENST00000591569.1 | n.283-551G>C | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152068Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000128 AC: 32AN: 250886Hom.: 1 AF XY: 0.0000957 AC XY: 13AN XY: 135794
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GnomAD4 exome AF: 0.0000280 AC: 41AN: 1461800Hom.: 1 Cov.: 31 AF XY: 0.0000234 AC XY: 17AN XY: 727202
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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 | Apr 12, 2022 | The c.889C>G (p.P297A) alteration is located in exon 9 (coding exon 8) of the EXOC3L2 gene. This alteration results from a C to G substitution at nucleotide position 889, causing the proline (P) at amino acid position 297 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
REVEL
Benign
Polyphen
1.0
.;D
Vest4
0.21
MutPred
0.40
.;Loss of sheet (P = 0.0457);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at