chr2-48582194-T-C

Position:

• chr2-48582194-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 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. 14/21 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

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.106218904).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STON1	NM_006873.4	c.1561T>C	p.Tyr521His	missense_variant	2/4	ENST00000404752.6
STON1-GTF2A1L	NM_001198593.2	c.1561T>C	p.Tyr521His	missense_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STON1	ENST00000404752.6	c.1561T>C	p.Tyr521His	missense_variant	2/4	1	NM_006873.4	P1
STON1	ENST00000406226.1	c.1561T>C	p.Tyr521His	missense_variant	3/5	1		P1
STON1	ENST00000649748.1	c.1561T>C	p.Tyr521His	missense_variant	3/5			P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 113

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2024

The c.1561T>C (p.Y521H) alteration is located in exon 3 (coding exon 1) of the STON1 gene. This alteration results from a T to C substitution at nucleotide position 1561, causing the tyrosine (Y) at amino acid position 521 to be replaced by a histidine (H). 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	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	12
DANN	Benign	0.88
DEOGEN2	Benign	0.017	T;T;T;.;.;.;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.69	.;.;T;.;T;T;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.5	M;M;M;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.6	.;N;N;N;N;N;N
REVEL	Benign	0.031
Sift	Benign	0.25	.;T;T;T;T;T;T
Sift4G	Uncertain	0.037	.;D;D;T;T;T;T
Polyphen		0.0050	B;B;B;B;.;B;.
Vest4		0.18, 0.18, 0.15, 0.15, 0.15, 0.14
MutPred		0.49		Gain of disorder (P = 0.0473);Gain of disorder (P = 0.0473);Gain of disorder (P = 0.0473);Gain of disorder (P = 0.0473);Gain of disorder (P = 0.0473);Gain of disorder (P = 0.0473);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

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-48809333;