chr2-48580986-G-T

Position:

• chr2-48580986-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006873.4(STON1):​c.353G>T​(p.Gly118Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00485 in 1,575,930 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0049 (67 hom.)
• Consequence: STON1 NM_006873.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.279

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004071653).
• BP6: Variant 2-48580986-G-T is Benign according to our data. Variant chr2-48580986-G-T is described in ClinVar as [Benign]. Clinvar id is 722414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00399 (607/152318) while in subpopulation SAS AF= 0.0297 (143/4822). AF 95% confidence interval is 0.0257. There are 5 homozygotes in gnomad4. There are 329 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STON1	NM_006873.4	c.353G>T	p.Gly118Val	missense_variant	2/4	ENST00000404752.6	NP_006864.2
STON1-GTF2A1L	NM_001198593.2	c.353G>T	p.Gly118Val	missense_variant	2/11		NP_001185522.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STON1	ENST00000404752.6	c.353G>T	p.Gly118Val	missense_variant	2/4	1	NM_006873.4	ENSP00000385273	P1
STON1	ENST00000406226.1	c.353G>T	p.Gly118Val	missense_variant	3/5	1		ENSP00000384615	P1
STON1	ENST00000649748.1	c.353G>T	p.Gly118Val	missense_variant	3/5			ENSP00000497745	P1

Frequencies

GnomAD3 genomes AF: 0.00398 AC: 605 AN: 152200 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0296

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00436

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00550 AC: 1169 AN: 212648 Hom.: 16 AF XY: 0.00657 AC XY: 747 AN XY: 113640

Gnomad AFR exome AF: 0.000887

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00295

Gnomad EAS exome AF: 0.000171

Gnomad SAS exome AF: 0.0283

Gnomad FIN exome AF: 0.000358

Gnomad NFE exome AF: 0.00437

Gnomad OTH exome AF: 0.00582

GnomAD4 exome AF: 0.00494 AC: 7039 AN: 1423612 Hom.: 67 Cov.: 36 AF XY: 0.00555 AC XY: 3910 AN XY: 705104

Gnomad4 AFR exome AF: 0.000837

Gnomad4 AMR exome AF: 0.00215

Gnomad4 ASJ exome AF: 0.00218

Gnomad4 EAS exome AF: 0.0000762

Gnomad4 SAS exome AF: 0.0274

Gnomad4 FIN exome AF: 0.000558

Gnomad4 NFE exome AF: 0.00391

Gnomad4 OTH exome AF: 0.00572

GnomAD4 genome AF: 0.00399 AC: 607 AN: 152318 Hom.: 5 Cov.: 33 AF XY: 0.00442 AC XY: 329 AN XY: 74482

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00576

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0297

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00438

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00447 Hom.: 5

Bravo AF: 0.00340

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00588 AC: 713

Asia WGS AF: 0.00960 AC: 33 AN: 3448

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	1.5
DANN	Uncertain	0.99
DEOGEN2	Benign	0.075	T;T;T;.;.;.;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.72	.;.;T;.;T;T;T
MetaRNN	Benign	0.0041	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;M;M;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.1	.;N;N;N;N;N;N
REVEL	Benign	0.030
Sift	Uncertain	0.0020	.;D;D;D;D;D;D
Sift4G	Uncertain	0.019	.;D;D;D;D;D;D
Polyphen		0.68	P;P;P;P;.;P;.
Vest4		0.28, 0.28, 0.27, 0.23
MVP		0.46
MPC		0.0064
ClinPred		0.023	T
GERP RS		1.9
Varity_R		0.057
gMVP		0.32

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

Other links and lift over

dbSNP: rs72824125; hg19: chr2-48808125;