8-38991538-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_078473.3(TM2D2):​c.439G>A​(p.Gly147Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,610,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

TM2D2
NM_078473.3 missense

Scores

13
3
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.80
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 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.921

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TM2D2NM_078473.3 linkuse as main transcriptc.439G>A p.Gly147Arg missense_variant 4/4 ENST00000456397.7 NP_510882.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TM2D2ENST00000456397.7 linkuse as main transcriptc.439G>A p.Gly147Arg missense_variant 4/41 NM_078473.3 ENSP00000416050 P1Q9BX73-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152044
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251140
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135740
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000144
AC:
21
AN:
1458954
Hom.:
0
Cov.:
32
AF XY:
0.0000193
AC XY:
14
AN XY:
726088
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:
0.0000696
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000135
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152044
Hom.:
0
Cov.:
31
AF XY:
0.0000404
AC XY:
3
AN XY:
74244
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000735
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

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 GeneticsNov 17, 2022The c.439G>A (p.G147R) alteration is located in exon 4 (coding exon 4) of the TM2D2 gene. This alteration results from a G to A substitution at nucleotide position 439, causing the glycine (G) at amino acid position 147 to be replaced by an arginine (R). 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
0.96
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.34
.;T;.;.
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
.;D;D;D
M_CAP
Benign
0.063
D
MetaRNN
Pathogenic
0.92
D;D;D;D
MetaSVM
Uncertain
-0.23
T
MutationAssessor
Pathogenic
3.6
.;H;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-6.7
D;D;D;D
REVEL
Pathogenic
0.68
Sift
Uncertain
0.0010
D;D;D;D
Sift4G
Uncertain
0.0040
D;D;D;.
Polyphen
1.0
D;D;D;.
Vest4
0.83
MutPred
0.78
.;Gain of solvent accessibility (P = 0.0171);.;.;
MVP
0.80
MPC
2.7
ClinPred
0.96
D
GERP RS
5.8
Varity_R
0.68
gMVP
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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: rs763565509; hg19: chr8-38849057; COSMIC: COSV56760793; COSMIC: COSV56760793; API