2-48582194-T-C

Variant names:

• chr2-48582194-T-C
• NM_006873.4:c.1561T>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.1561T>C​(p.Tyr521His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STON1 NM_006873.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.12
• 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=0.106218904).

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.1561T>C	p.Tyr521His	missense	Exon 2 of 4	NP_006864.2
	STON1-GTF2A1L	NM_172311.3		c.1561T>C	p.Tyr521His	missense	Exon 2 of 11	NP_758515.1	Q53S48
	STON1-GTF2A1L	NM_001198593.2		c.1561T>C	p.Tyr521His	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.1561T>C	p.Tyr521His	missense	Exon 2 of 4	ENSP00000385273.1	Q9Y6Q2-1
	STON1-GTF2A1L	ENST00000394754.5	TSL:1	c.1561T>C	p.Tyr521His	missense	Exon 2 of 11	ENSP00000378236.1	Q53S48
	STON1-GTF2A1L	ENST00000394751.5	TSL:2	c.1561T>C	p.Tyr521His	missense	Exon 1 of 8	ENSP00000378234.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 113

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	12
DANN	Benign	0.88
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.1
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.031
Sift	Benign	0.25	T
Sift4G	Uncertain	0.037	D
Polyphen		0.0050	B
Vest4		0.18
MutPred		0.49		Gain of disorder (P = 0.0473)
MVP		0.17
MPC		0.0036
ClinPred		0.21	T
GERP RS		1.6
Varity_R		0.039
gMVP		0.60
Mutation Taster		=87/13	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

hg19: chr2-48809333;