chr8-38995364-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_078473.3(TM2D2):ā€‹c.269T>Cā€‹(p.Val90Ala) 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

TM2D2
NM_078473.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.40
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.04799196).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TM2D2NM_078473.3 linkuse as main transcriptc.269T>C p.Val90Ala missense_variant 2/4 ENST00000456397.7 NP_510882.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TM2D2ENST00000456397.7 linkuse as main transcriptc.269T>C p.Val90Ala missense_variant 2/41 NM_078473.3 ENSP00000416050 P1Q9BX73-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1455318
Hom.:
0
Cov.:
29
AF XY:
0.00
AC XY:
0
AN XY:
723890
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

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 GeneticsSep 27, 2022The c.269T>C (p.V90A) alteration is located in exon 2 (coding exon 2) of the TM2D2 gene. This alteration results from a T to C substitution at nucleotide position 269, causing the valine (V) at amino acid position 90 to be replaced by an alanine (A). 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
0.076
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.46
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.0026
.;T;.;.;.
Eigen
Benign
-0.44
Eigen_PC
Benign
-0.21
FATHMM_MKL
Benign
0.56
D
LIST_S2
Benign
0.85
.;T;D;D;T
M_CAP
Benign
0.00096
T
MetaRNN
Benign
0.048
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.17
.;N;.;.;.
MutationTaster
Benign
0.93
N;N;N;N
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
1.3
N;N;N;N;N
REVEL
Benign
0.13
Sift
Benign
0.77
T;T;T;T;T
Sift4G
Benign
0.79
T;T;T;.;.
Polyphen
0.0010
B;B;B;.;.
Vest4
0.18
MutPred
0.29
.;Gain of relative solvent accessibility (P = 0.0166);.;.;.;
MVP
0.16
MPC
0.053
ClinPred
0.10
T
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.044
gMVP
0.67

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: rs1835730877; hg19: chr8-38852883; API