chr2-672826-G-A

Position:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_152834.4(TMEM18):​c.215C>T​(p.Ala72Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000503 in 1,479,316 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00050 ( 3 hom. )

Consequence

TMEM18
NM_152834.4 missense

Scores

19

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.81
Variant links:
Genes affected
TMEM18 (HGNC:25257): (transmembrane protein 18) Predicted to enable DNA binding activity. Involved in cell migration. Located in nuclear membrane. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.015538156).
BP6
Variant 2-672826-G-A is Benign according to our data. Variant chr2-672826-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2400369.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TMEM18NM_152834.4 linkuse as main transcriptc.215C>T p.Ala72Val missense_variant 3/5 ENST00000281017.8 NP_690047.2
TMEM18NM_001352681.1 linkuse as main transcriptc.224C>T p.Ala75Val missense_variant 3/5 NP_001339610.1
TMEM18NM_001352680.2 linkuse as main transcriptc.176C>T p.Ala59Val missense_variant 4/6 NP_001339609.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TMEM18ENST00000281017.8 linkuse as main transcriptc.215C>T p.Ala72Val missense_variant 3/51 NM_152834.4 ENSP00000281017 P1Q96B42-1

Frequencies

GnomAD3 genomes
AF:
0.000526
AC:
80
AN:
152198
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
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:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00110
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000623
AC:
99
AN:
158986
Hom.:
1
AF XY:
0.000543
AC XY:
48
AN XY:
88420
show subpopulations
Gnomad AFR exome
AF:
0.0000964
Gnomad AMR exome
AF:
0.0000869
Gnomad ASJ exome
AF:
0.000165
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000305
Gnomad NFE exome
AF:
0.00107
Gnomad OTH exome
AF:
0.000633
GnomAD4 exome
AF:
0.000500
AC:
664
AN:
1327000
Hom.:
3
Cov.:
31
AF XY:
0.000529
AC XY:
345
AN XY:
651850
show subpopulations
Gnomad4 AFR exome
AF:
0.0000385
Gnomad4 AMR exome
AF:
0.000103
Gnomad4 ASJ exome
AF:
0.0000457
Gnomad4 EAS exome
AF:
0.0000320
Gnomad4 SAS exome
AF:
0.0000153
Gnomad4 FIN exome
AF:
0.000366
Gnomad4 NFE exome
AF:
0.000590
Gnomad4 OTH exome
AF:
0.000330
GnomAD4 genome
AF:
0.000525
AC:
80
AN:
152316
Hom.:
0
Cov.:
33
AF XY:
0.000403
AC XY:
30
AN XY:
74476
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.00110
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000891
Hom.:
0
Bravo
AF:
0.000408
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000581
AC:
5
ExAC
AF:
0.000544
AC:
66

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJan 07, 2022This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.049
BayesDel_addAF
Benign
-0.57
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
1.7
DANN
Benign
0.63
DEOGEN2
Benign
0.0077
T;.;T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.059
N
LIST_S2
Benign
0.71
T;T;T
M_CAP
Benign
0.0041
T
MetaRNN
Benign
0.016
T;T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
-2.1
N;.;.
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.36
T
PROVEAN
Benign
1.5
N;N;N
REVEL
Benign
0.035
Sift
Benign
0.81
T;T;T
Sift4G
Benign
0.62
T;T;T
Polyphen
0.0040
B;.;.
Vest4
0.25
MVP
0.081
MPC
0.15
ClinPred
0.0035
T
GERP RS
1.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.011
gMVP
0.25

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs149085075; hg19: chr2-672826; COSMIC: COSV99028646; COSMIC: COSV99028646; API