2-48580809-G-C

Variant names:

• chr2-48580809-G-C
• rs765085882
• NM_006873.4:c.176G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006873.4(STON1):​c.176G>C​(p.Ser59Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000572 in 1,399,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. S59N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: STON1 NM_006873.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.80
• Publications: 0 publications found

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]

STON1-GTF2A1L (HGNC:30651): (STON1-GTF2A1L readthrough) STON1-GTF2A1L mRNAs are infrequent but naturally occurring read-through products of the neighboring STON1 and GTF2A1L genes. These transcripts encode fusion proteins composed of the vast majority of each of the individual elements, stonin 1 and general transcription factor IIA, 1-like. Alternative splicing results in multiple transcript variants. The significance of these read-through variants and the function of the resulting protein products have not yet been determined. [provided by RefSeq, Oct 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18061385).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006873.4. 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
	STON1	NM_006873.4	MANE Select	c.176G>C	p.Ser59Thr	missense	Exon 2 of 4	NP_006864.2
	STON1-GTF2A1L	NM_172311.3		c.176G>C	p.Ser59Thr	missense	Exon 2 of 11	NP_758515.1	Q53S48
	STON1-GTF2A1L	NM_001198593.2		c.176G>C	p.Ser59Thr	missense	Exon 2 of 11	NP_001185522.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STON1	ENST00000404752.6	TSL:1 MANE Select	c.176G>C	p.Ser59Thr	missense	Exon 2 of 4	ENSP00000385273.1	Q9Y6Q2-1
	STON1-GTF2A1L	ENST00000394754.5	TSL:1	c.176G>C	p.Ser59Thr	missense	Exon 2 of 11	ENSP00000378236.1	Q53S48
	STON1-GTF2A1L	ENST00000394751.5	TSL:2	c.176G>C	p.Ser59Thr	missense	Exon 1 of 8	ENSP00000378234.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000572 AC: 8 AN: 1399498 Hom.: 0 Cov.: 36 AF XY: 0.00000724 AC XY: 5 AN XY: 690920

African (AFR) AF: 0.00 AC: 0 AN: 31248

American (AMR) AF: 0.00 AC: 0 AN: 35114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22666

East Asian (EAS) AF: 0.00 AC: 0 AN: 38084

South Asian (SAS) AF: 0.00 AC: 0 AN: 74420

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5506

European-Non Finnish (NFE) AF: 0.00000739 AC: 8 AN: 1082836

Other (OTH) AF: 0.00 AC: 0 AN: 57932

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.026	T
Eigen	Benign	0.011
Eigen_PC	Benign	0.011
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.8
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.055
Sift	Benign	0.043	D
Sift4G	Benign	0.26	T
Polyphen		0.79	P
Vest4		0.30
MutPred		0.13		Gain of catalytic residue at S59 (P = 0.042)
MVP		0.38
MPC		0.0058
ClinPred		0.68	D
GERP RS		3.5
PromoterAI		-0.0074	Neutral
Varity_R		0.061
gMVP		0.35
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs765085882; hg19: chr2-48807948;