Variant 1-115062183-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005725.6(TSPAN2):c.222C>A(p.Phe74Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000234 in 1,601,328 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

TSPAN2
NM_005725.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.45

Variant links:

Genes affected

TSPAN2 (HGNC:20659): (tetraspanin 2) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

TSPAN2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TSPAN2	NM_005725.6 linkuse as main transcript	c.222C>A	p.Phe74Leu	missense_variant	3/8	ENST00000369516.7
TSPAN2	NM_001308315.2 linkuse as main transcript	c.222C>A	p.Phe74Leu	missense_variant	3/7
TSPAN2	NM_001308316.2 linkuse as main transcript	c.222C>A	p.Phe74Leu	missense_variant	3/7
TSPAN2	XM_016999996.2 linkuse as main transcript	c.222C>A	p.Phe74Leu	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPAN2	ENST00000369516.7 linkuse as main transcript	c.222C>A	p.Phe74Leu	missense_variant	3/8	1	NM_005725.6	P1	O60636-1
TSPAN2	ENST00000433172.3 linkuse as main transcript	c.204C>A	p.Phe68Leu	missense_variant	3/7	1
TSPAN2	ENST00000369515.6 linkuse as main transcript	c.222C>A	p.Phe74Leu	missense_variant	3/7	3

Frequencies

GnomAD3 genomes

AF:

0.000139

AC:

AN:

151586

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000485

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:

0.000280

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000565

AC:

AN:

229922

Hom.:

AF XY:

0.0000646

AC XY:

AN XY:

123774

show subpopulations

Gnomad AFR exome

AF:

0.000212

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:

0.0000969

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000244

AC:

354

AN:

1449626

Hom.:

Cov.:

AF XY:

0.000250

AC XY:

180

AN XY:

719764

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000315

Gnomad4 OTH exome

AF:

0.0000834

GnomAD4 genome

AF:

0.000138

AC:

AN:

151702

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74140

show subpopulations

Gnomad4 AFR

AF:

0.0000484

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:

0.000280

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000911

Hom.:

Bravo

AF:

0.000113

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000495

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2021

The c.222C>A (p.F74L) alteration is located in exon 3 (coding exon 3) of the TSPAN2 gene. This alteration results from a C to A substitution at nucleotide position 222, causing the phenylalanine (F) at amino acid position 74 to be replaced by a leucine (L). 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

Pathogenic

0.90

BayesDel_addAF

Benign

-0.093

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

T;.;.

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Benign

0.043

MetaRNN

Uncertain

0.64

D;D;D

MetaSVM

Benign

-0.32

MutationAssessor

Uncertain

2.8

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-5.7

D;D;D

REVEL

Uncertain

0.53

Sift

Uncertain

0.013

D;D;D

Sift4G

Uncertain

0.034

D;D;D

Polyphen

0.46

P;.;.

Vest4

0.57

MutPred

0.76

Loss of catalytic residue at F74 (P = 0.1414);Loss of catalytic residue at F74 (P = 0.1414);.;

MVP

0.50

MPC

0.14

ClinPred

0.51

GERP RS

5.6

Varity_R

0.74

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over