Genetic Variant TSPAN2:p.Thr200Arg (chr1-115053380-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_005725.6(TSPAN2):c.599C>G(p.Thr200Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. T200M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TSPAN2
NM_005725.6 missense, splice_region

Scores

Splicing: ADA: 0.5869

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.65

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPAN2	NM_005725.6 link	c.599C>G	p.Thr200Arg	missense_variant, splice_region_variant	Exon 7 of 8	ENST00000369516.7	NP_005716.2	O60636-1B2RD31
TSPAN2	NM_001308315.2 link	c.524C>G	p.Thr175Arg	missense_variant, splice_region_variant	Exon 6 of 7		NP_001295244.1	B1AKP1
TSPAN2	NM_001308316.2 link	c.517-2825C>G		intron_variant	Intron 6 of 6		NP_001295245.1	O60636-2
TSPAN2	XM_016999996.2 link	c.442-2825C>G		intron_variant	Intron 5 of 5		XP_016855485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TSPAN2	ENST00000369516.7 link	c.599C>G	p.Thr200Arg	missense_variant, splice_region_variant	Exon 7 of 8	1	NM_005725.6	ENSP00000358529.2	O60636-1
TSPAN2	ENST00000433172.3 link	c.499-2825C>G		intron_variant	Intron 6 of 6	1		ENSP00000415256.1	B1AKP2
TSPAN2	ENST00000369515.6 link	c.524C>G	p.Thr175Arg	missense_variant, splice_region_variant	Exon 6 of 7	3		ENSP00000358528.2	B1AKP1
TSPAN2	ENST00000491992.1 link	n.352C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 4	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461444

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727026

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111674

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

T;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.93

D;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Uncertain

-0.10

MutationAssessor

Uncertain

2.1

M;.

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.1

N;N

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.054

T;D

Polyphen

1.0

D;.

Vest4

0.76

MutPred

0.77

Gain of methylation at T200 (P = 0.0594);.;

MVP

0.72

MPC

0.49

ClinPred

0.94

GERP RS

4.8

Varity_R

0.91

gMVP

0.97

Mutation Taster

=63/37

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.59

dbscSNV1_RF

Benign

0.40

SpliceAI score (max)

0.45

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.45

Position offset: -1

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.

1-115053380-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over