19-46838532-T-C
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate
The NM_004069.6(AP2S1):c.344A>G(p.Asp115Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 31)
Consequence
AP2S1
NM_004069.6 missense
NM_004069.6 missense
Scores
7
7
1
Clinical Significance
Conservation
PhyloP100: 5.77
Genes affected
AP2S1 (HGNC:565): (adaptor related protein complex 2 subunit sigma 1) One of two major clathrin-associated adaptor complexes, AP-2, is a heterotetramer which is associated with the plasma membrane. This complex is composed of two large chains, a medium chain, and a small chain. This gene encodes the small chain of this complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM1
In a chain AP-2 complex subunit sigma (size 141) in uniprot entity AP2S1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_004069.6
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, AP2S1
PP3
MetaRNN computational evidence supports a deleterious effect, 0.849
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AP2S1 | NM_004069.6 | c.344A>G | p.Asp115Gly | missense_variant | 5/5 | ENST00000263270.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AP2S1 | ENST00000263270.11 | c.344A>G | p.Asp115Gly | missense_variant | 5/5 | 1 | NM_004069.6 | P4 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 11, 2021 | The c.344A>G (p.D115G) alteration is located in exon 5 (coding exon 5) of the AP2S1 gene. This alteration results from a A to G substitution at nucleotide position 344, causing the aspartic acid (D) at amino acid position 115 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
REVEL
Uncertain
Sift4G
Uncertain
D;D;D;T;D;D;D
Polyphen
0.031, 0.55
.;.;.;.;B;.;P
Vest4
MutPred
0.80
.;.;.;.;Loss of phosphorylation at Y111 (P = 0.2865);.;.;
MVP
MPC
2.2
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.