chr2-48580809-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006873.4(STON1):​c.176G>A​(p.Ser59Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000374 in 1,551,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

STON1
NM_006873.4 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.80
Variant links:
Genes affected
STON1 (HGNC:17003): (stonin 1) Endocytosis of cell surface proteins is mediated by a complex molecular machinery that assembles on the inner surface of the plasma membrane. This gene encodes one of two human homologs of the Drosophila melanogaster stoned B protein. This protein is related to components of the endocytic machinery and exhibits a modular structure consisting of an N-terminal proline-rich domain, a central region of homology specific to the human stoned B-like proteins, and a C-terminal region homologous to the mu subunits of adaptor protein (AP) complexes. Read-through transcription of this gene into the neighboring downstream gene, which encodes TFIIA-alpha/beta-like factor, generates a transcript (SALF), which encodes a fusion protein comprised of sequence sharing identity with each individual gene product. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2010]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.05324307).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
STON1NM_006873.4 linkuse as main transcriptc.176G>A p.Ser59Asn missense_variant 2/4 ENST00000404752.6
STON1-GTF2A1LNM_001198593.2 linkuse as main transcriptc.176G>A p.Ser59Asn missense_variant 2/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
STON1ENST00000404752.6 linkuse as main transcriptc.176G>A p.Ser59Asn missense_variant 2/41 NM_006873.4 P1Q9Y6Q2-1
STON1ENST00000406226.1 linkuse as main transcriptc.176G>A p.Ser59Asn missense_variant 3/51 P1Q9Y6Q2-1
STON1ENST00000649748.1 linkuse as main transcriptc.176G>A p.Ser59Asn missense_variant 3/5 P1Q9Y6Q2-1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152156
Hom.:
0
Cov.:
33
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:
0.000471
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000111
AC:
22
AN:
197390
Hom.:
0
AF XY:
0.0000950
AC XY:
10
AN XY:
105290
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000990
Gnomad NFE exome
AF:
0.0000319
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000372
AC:
52
AN:
1399498
Hom.:
0
Cov.:
36
AF XY:
0.0000362
AC XY:
25
AN XY:
690920
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:
0.000909
Gnomad4 NFE exome
AF:
0.00000462
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152156
Hom.:
0
Cov.:
33
AF XY:
0.0000404
AC XY:
3
AN XY:
74330
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:
0.000471
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000478
Bravo
AF:
0.00000756
ExAC
AF:
0.0000495
AC:
6

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 submitterclinical testingAmbry GeneticsMay 11, 2022The c.176G>A (p.S59N) alteration is located in exon 3 (coding exon 1) of the STON1 gene. This alteration results from a G to A substitution at nucleotide position 176, causing the serine (S) at amino acid position 59 to be replaced by an asparagine (N). 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
0.11
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.65
CADD
Benign
17
DANN
Uncertain
0.98
DEOGEN2
Benign
0.091
T;T;T;.;.;.;.
Eigen
Benign
-0.078
Eigen_PC
Benign
-0.048
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.69
.;.;T;.;T;T;T
M_CAP
Benign
0.0057
T
MetaRNN
Benign
0.053
T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.4
M;M;M;.;.;.;.
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-0.49
.;N;N;N;N;N;N
REVEL
Benign
0.064
Sift
Uncertain
0.023
.;D;D;D;D;D;D
Sift4G
Benign
0.31
.;T;T;T;T;T;T
Polyphen
0.65
P;P;P;B;.;B;.
Vest4
0.18, 0.18, 0.16, 0.18, 0.17, 0.19
MutPred
0.16
Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);
MVP
0.35
MPC
0.0038
ClinPred
0.13
T
GERP RS
3.5
Varity_R
0.051
gMVP
0.34

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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.

Other links and lift over

dbSNP: rs765085882; hg19: chr2-48807948; API