2-48595280-T-G

Variant names:

• chr2-48595280-T-G
• rs770568145
• NM_006873.4:c.2186T>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006873.4(STON1):​c.2186T>G​(p.Ile729Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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. I729T) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: STON1 NM_006873.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.43

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

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=0.055168986).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STON1	NM_006873.4	c.2186T>G	p.Ile729Ser	missense_variant	Exon 4 of 4	ENST00000404752.6	NP_006864.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STON1	ENST00000404752.6	c.2186T>G	p.Ile729Ser	missense_variant	Exon 4 of 4	1	NM_006873.4	ENSP00000385273.1
STON1-GTF2A1L	ENST00000394754.5	c.2133+3425T>G		intron_variant	Intron 3 of 10	1		ENSP00000378236.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251182 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135768

Gnomad AFR exome AF: 0.0000615

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: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74320

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	20
DANN	Benign	0.85
DEOGEN2	Benign	0.0039	T;T;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.58	.;.;T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.055	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;N
PROVEAN	Benign	0.040	.;N;N
REVEL	Benign	0.039
Sift	Benign	0.17	.;T;T
Sift4G	Benign	0.12	.;T;T
Polyphen		0.0020	B;B;B
Vest4		0.062, 0.063
MutPred		0.15		Gain of disorder (P = 0.0447);Gain of disorder (P = 0.0447);Gain of disorder (P = 0.0447);
MVP		0.37
ClinPred		0.077	T
GERP RS		3.8
Varity_R		0.057
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs770568145; hg19: chr2-48822419;