rs2277698

chr17-78870935-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_003255.5(TIMP2):c.303G>A(p.Ser101=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 1,611,508 control chromosomes in the GnomAD database, including 13,842 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1205 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12637 hom.)
• Consequence: TIMP2 NM_003255.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.10

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 17-78870935-C-T is Benign according to our data. Variant chr17-78870935-C-T is described in ClinVar as [Benign]. Clinvar id is 3059644.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMP2	NM_003255.5	c.303G>A	p.Ser101=	synonymous_variant	3/5	ENST00000262768.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMP2	ENST00000262768.11	c.303G>A	p.Ser101=	synonymous_variant	3/5	1	NM_003255.5	P1

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17850 AN: 152102 Hom.: 1208 Cov.: 32

Gnomad AFR AF: 0.0946

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.114

GnomAD3 exomes AF: 0.133 AC: 33339 AN: 249848 Hom.: 2663 AF XY: 0.138 AC XY: 18651 AN XY: 134966

Gnomad AFR exome AF: 0.0923

Gnomad AMR exome AF: 0.0874

Gnomad ASJ exome AF: 0.100

Gnomad EAS exome AF: 0.225

Gnomad SAS exome AF: 0.233

Gnomad FIN exome AF: 0.125

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.126 AC: 184176 AN: 1459288 Hom.: 12637 Cov.: 31 AF XY: 0.129 AC XY: 93521 AN XY: 725800

Gnomad4 AFR exome AF: 0.0953

Gnomad4 AMR exome AF: 0.0910

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.176

Gnomad4 SAS exome AF: 0.225

Gnomad4 FIN exome AF: 0.122

Gnomad4 NFE exome AF: 0.119

Gnomad4 OTH exome AF: 0.133

GnomAD4 genome AF: 0.117 AC: 17851 AN: 152220 Hom.: 1205 Cov.: 32 AF XY: 0.118 AC XY: 8794 AN XY: 74418

Gnomad4 AFR AF: 0.0946

Gnomad4 AMR AF: 0.104

Gnomad4 ASJ AF: 0.103

Gnomad4 EAS AF: 0.224

Gnomad4 SAS AF: 0.223

Gnomad4 FIN AF: 0.121

Gnomad4 NFE AF: 0.117

Gnomad4 OTH AF: 0.118

Alfa AF: 0.115 Hom.: 1332

Bravo AF: 0.115

Asia WGS AF: 0.203 AC: 707 AN: 3478

EpiCase AF: 0.119

EpiControl AF: 0.113

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

TIMP2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 11, 2019

This 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	-0.23
Cadd	Benign	7.8
Dann	Benign	0.77
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

Other links and lift over

dbSNP: rs2277698; hg19: chr17-76867017; COSMIC: COSV53163572;