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17-78925053-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_003255.5(TIMP2):c.36C>T(p.Leu12=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0328 in 1,184,470 control chromosomes in the GnomAD database, including 726 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.024 ( 74 hom., cov: 29)
Exomes 𝑓: 0.034 ( 652 hom. )

Consequence

TIMP2
NM_003255.5 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.612
Variant links:
Genes affected
TIMP2 (HGNC:11821): (TIMP metallopeptidase inhibitor 2) This gene is a member of the TIMP gene family. The proteins encoded by this gene family are natural inhibitors of the matrix metalloproteinases, a group of peptidases involved in degradation of the extracellular matrix. In addition to an inhibitory role against metalloproteinases, the encoded protein has a unique role among TIMP family members in its ability to directly suppress the proliferation of endothelial cells. As a result, the encoded protein may be critical to the maintenance of tissue homeostasis by suppressing the proliferation of quiescent tissues in response to angiogenic factors, and by inhibiting protease activity in tissues undergoing remodelling of the extracellular matrix. [provided by RefSeq, Jul 2008]

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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=-0.68).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-78925053-G-A is Benign according to our data. Variant chr17-78925053-G-A is described in ClinVar as [Benign]. Clinvar id is 3038074.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=0.612 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0243 (3589/147722) while in subpopulation NFE AF= 0.0359 (2388/66532). AF 95% confidence interval is 0.0347. There are 74 homozygotes in gnomad4. There are 1844 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 74 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TIMP2NM_003255.5 linkuse as main transcriptc.36C>T p.Leu12= synonymous_variant 1/5 ENST00000262768.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TIMP2ENST00000262768.11 linkuse as main transcriptc.36C>T p.Leu12= synonymous_variant 1/51 NM_003255.5 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0243
AC:
3590
AN:
147618
Hom.:
74
Cov.:
29
show subpopulations
Gnomad AFR
AF:
0.00566
Gnomad AMI
AF:
0.00561
Gnomad AMR
AF:
0.0134
Gnomad ASJ
AF:
0.0190
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.0294
Gnomad FIN
AF:
0.0574
Gnomad MID
AF:
0.0159
Gnomad NFE
AF:
0.0359
Gnomad OTH
AF:
0.0206
GnomAD3 exomes
AF:
0.0560
AC:
434
AN:
7754
Hom.:
17
AF XY:
0.0578
AC XY:
295
AN XY:
5104
show subpopulations
Gnomad AFR exome
AF:
0.0116
Gnomad AMR exome
AF:
0.0312
Gnomad ASJ exome
AF:
0.0280
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0571
Gnomad FIN exome
AF:
0.0885
Gnomad NFE exome
AF:
0.0539
Gnomad OTH exome
AF:
0.0556
GnomAD4 exome
AF:
0.0340
AC:
35288
AN:
1036748
Hom.:
652
Cov.:
29
AF XY:
0.0343
AC XY:
16915
AN XY:
493266
show subpopulations
Gnomad4 AFR exome
AF:
0.00411
Gnomad4 AMR exome
AF:
0.0118
Gnomad4 ASJ exome
AF:
0.0183
Gnomad4 EAS exome
AF:
0.000139
Gnomad4 SAS exome
AF:
0.0335
Gnomad4 FIN exome
AF:
0.0537
Gnomad4 NFE exome
AF:
0.0358
Gnomad4 OTH exome
AF:
0.0298
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0243
AC:
3589
AN:
147722
Hom.:
74
Cov.:
29
AF XY:
0.0256
AC XY:
1844
AN XY:
72052
show subpopulations
Gnomad4 AFR
AF:
0.00565
Gnomad4 AMR
AF:
0.0134
Gnomad4 ASJ
AF:
0.0190
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.0294
Gnomad4 FIN
AF:
0.0574
Gnomad4 NFE
AF:
0.0359
Gnomad4 OTH
AF:
0.0199
Alfa
AF:
0.0288
Hom.:
5
Bravo
AF:
0.0198

ClinVar

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

Submissions by phenotype

TIMP2-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesOct 21, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.68
Cadd
Benign
14
Dann
Benign
0.92

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: rs577686887; hg19: chr17-76921135; API