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2-218275565-G-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_022152.6(TMBIM1):c.846C>G(p.Pro282=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.391 in 1,613,430 control chromosomes in the GnomAD database, including 125,040 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.36 ( 10013 hom., cov: 33)
Exomes 𝑓: 0.40 ( 115027 hom. )

Consequence

TMBIM1
NM_022152.6 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -9.03
Variant links:
Genes affected
TMBIM1 (HGNC:23410): (transmembrane BAX inhibitor motif containing 1) Enables death receptor binding activity. Involved in negative regulation of Fas signaling pathway; negative regulation of extrinsic apoptotic signaling pathway via death domain receptors; and negative regulation of protein localization to plasma membrane. Located in Golgi apparatus; endosome membrane; and lysosomal membrane. [provided by Alliance of Genome Resources, Apr 2022]
PNKD (HGNC:9153): (PNKD metallo-beta-lactamase domain containing) This gene is thought to play a role in the regulation of myofibrillogenesis. Mutations in this gene have been associated with the movement disorder paroxysmal non-kinesigenic dyskinesia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 2-218275565-G-C is Benign according to our data. Variant chr2-218275565-G-C is described in ClinVar as [Benign]. Clinvar id is 1264824.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-9.03 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.423 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TMBIM1NM_022152.6 linkuse as main transcriptc.846C>G p.Pro282= synonymous_variant 12/12 ENST00000258412.8
PNKDNM_015488.5 linkuse as main transcriptc.236+4016G>C intron_variant ENST00000273077.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TMBIM1ENST00000258412.8 linkuse as main transcriptc.846C>G p.Pro282= synonymous_variant 12/121 NM_022152.6 P1
PNKDENST00000273077.9 linkuse as main transcriptc.236+4016G>C intron_variant 1 NM_015488.5 Q8N490-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.356
AC:
54151
AN:
152008
Hom.:
10012
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.255
Gnomad AMI
AF:
0.429
Gnomad AMR
AF:
0.432
Gnomad ASJ
AF:
0.393
Gnomad EAS
AF:
0.396
Gnomad SAS
AF:
0.354
Gnomad FIN
AF:
0.285
Gnomad MID
AF:
0.506
Gnomad NFE
AF:
0.405
Gnomad OTH
AF:
0.392
GnomAD3 exomes
AF:
0.384
AC:
96341
AN:
250646
Hom.:
18822
AF XY:
0.384
AC XY:
52052
AN XY:
135494
show subpopulations
Gnomad AFR exome
AF:
0.246
Gnomad AMR exome
AF:
0.454
Gnomad ASJ exome
AF:
0.390
Gnomad EAS exome
AF:
0.386
Gnomad SAS exome
AF:
0.352
Gnomad FIN exome
AF:
0.300
Gnomad NFE exome
AF:
0.406
Gnomad OTH exome
AF:
0.409
GnomAD4 exome
AF:
0.395
AC:
577380
AN:
1461304
Hom.:
115027
Cov.:
46
AF XY:
0.394
AC XY:
286722
AN XY:
726950
show subpopulations
Gnomad4 AFR exome
AF:
0.247
Gnomad4 AMR exome
AF:
0.448
Gnomad4 ASJ exome
AF:
0.388
Gnomad4 EAS exome
AF:
0.388
Gnomad4 SAS exome
AF:
0.351
Gnomad4 FIN exome
AF:
0.302
Gnomad4 NFE exome
AF:
0.405
Gnomad4 OTH exome
AF:
0.396
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.356
AC:
54165
AN:
152126
Hom.:
10013
Cov.:
33
AF XY:
0.354
AC XY:
26337
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.255
Gnomad4 AMR
AF:
0.432
Gnomad4 ASJ
AF:
0.393
Gnomad4 EAS
AF:
0.395
Gnomad4 SAS
AF:
0.354
Gnomad4 FIN
AF:
0.285
Gnomad4 NFE
AF:
0.405
Gnomad4 OTH
AF:
0.392
Alfa
AF:
0.316
Hom.:
1406
Bravo
AF:
0.363
EpiCase
AF:
0.404
EpiControl
AF:
0.415

ClinVar

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

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxMay 14, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.85
Cadd
Benign
0.0090
Dann
Benign
0.72
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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: rs2292550; hg19: chr2-219140288; COSMIC: COSV50310933; COSMIC: COSV50310933; API