8-38993593-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_078473.3(TM2D2):ā€‹c.383A>Gā€‹(p.Glu128Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000348 in 1,613,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000092 ( 0 hom., cov: 33)
Exomes š‘“: 0.00037 ( 0 hom. )

Consequence

TM2D2
NM_078473.3 missense

Scores

8
6
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.15
Variant links:
Genes affected
TM2D2 (HGNC:24127): (TM2 domain containing 2) The protein encoded by this gene contains a structural module related to that of the seven transmembrane domain G protein-coupled receptor superfamily. This protein has sequence and structural similarities to the beta-amyloid binding protein (BBP), but, unlike BBP, it does not regulate a response to beta-amyloid peptide. This protein may have regulatory roles in cell death or proliferation signal cascades. This gene has multiple alternatively spliced transcript variants which encode two different isoforms. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.808

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TM2D2NM_078473.3 linkuse as main transcriptc.383A>G p.Glu128Gly missense_variant 3/4 ENST00000456397.7 NP_510882.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TM2D2ENST00000456397.7 linkuse as main transcriptc.383A>G p.Glu128Gly missense_variant 3/41 NM_078473.3 ENSP00000416050 P1Q9BX73-1

Frequencies

GnomAD3 genomes
AF:
0.0000920
AC:
14
AN:
152226
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.000147
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.000135
AC:
34
AN:
251462
Hom.:
0
AF XY:
0.000147
AC XY:
20
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.0000578
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:
0.000220
Gnomad OTH exome
AF:
0.000651
GnomAD4 exome
AF:
0.000374
AC:
547
AN:
1461662
Hom.:
0
Cov.:
30
AF XY:
0.000370
AC XY:
269
AN XY:
727138
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000466
Gnomad4 OTH exome
AF:
0.000364
GnomAD4 genome
AF:
0.0000920
AC:
14
AN:
152226
Hom.:
0
Cov.:
33
AF XY:
0.0000807
AC XY:
6
AN XY:
74384
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.00143
Alfa
AF:
0.000218
Hom.:
0
Bravo
AF:
0.000144
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000107
AC:
13
EpiCase
AF:
0.000273
EpiControl
AF:
0.000533

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 submitterclinical testingAmbry GeneticsApr 13, 2022The c.383A>G (p.E128G) alteration is located in exon 3 (coding exon 3) of the TM2D2 gene. This alteration results from a A to G substitution at nucleotide position 383, causing the glutamic acid (E) at amino acid position 128 to be replaced by a glycine (G). 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
0.77
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Pathogenic
0.19
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.28
.;T;.;.
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.92
.;D;D;D
M_CAP
Benign
0.037
D
MetaRNN
Pathogenic
0.81
D;D;D;D
MetaSVM
Benign
-0.45
T
MutationAssessor
Uncertain
2.9
.;M;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.59
T
PROVEAN
Pathogenic
-6.8
D;D;D;D
REVEL
Uncertain
0.48
Sift
Benign
0.035
D;D;D;D
Sift4G
Uncertain
0.0040
D;D;D;.
Polyphen
1.0
D;D;D;.
Vest4
0.79
MVP
0.71
MPC
0.31
ClinPred
0.85
D
GERP RS
5.7
Varity_R
0.60
gMVP
0.95

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

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

Other links and lift over

dbSNP: rs199739639; hg19: chr8-38851112; COSMIC: COSV100206049; COSMIC: COSV100206049; API