rs11068997

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_057169.5(GIT2):c.1655C>T(p.Ala552Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0348 in 1,529,976 control chromosomes in the GnomAD database, including 1,261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.052 ( 293 hom., cov: 32)

Exomes 𝑓: 0.033 ( 968 hom. )

Consequence

GIT2
NM_057169.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 7.69

Publications

15 publications found

Variant links:

Genes affected

GIT2 (HGNC:4273): (GIT ArfGAP 2) This gene encodes a member of the GIT protein family, which interact with G protein-coupled receptor kinases and possess ADP-ribosylation factor (ARF) GTPase-activating protein (GAP) activity. GIT proteins traffic between cytoplasmic complexes, focal adhesions, and the cell periphery, and interact with Pak interacting exchange factor beta (PIX) to form large oligomeric complexes that transiently recruit other proteins. GIT proteins regulate cytoskeletal dynamics and participate in receptor internalization and membrane trafficking. This gene has been shown to repress lamellipodial extension and focal adhesion turnover, and is thought to regulate cell motility. This gene undergoes extensive alternative splicing to generate multiple isoforms, but the full-length nature of some of these variants has not been determined. The various isoforms have functional differences, with respect to ARF GAP activity and to G protein-coupled receptor kinase 2 binding. [provided by RefSeq, Sep 2008]

GIT2 links:

TCHP (HGNC:28135): (trichoplein keratin filament binding) Involved in apoptotic process; negative regulation of cell growth; and negative regulation of cilium assembly. Located in several cellular components, including apical cortex; cytoskeleton; and mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

TCHP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015673637).

BP6

Variant 12-109945336-G-A is Benign according to our data. Variant chr12-109945336-G-A is described in ClinVar as Benign. ClinVar VariationId is 1276394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GIT2	NM_057169.5 link	c.1655C>T	p.Ala552Val	missense_variant	Exon 16 of 20	ENST00000355312.8	NP_476510.1	Q14161-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GIT2	ENST00000355312.8 link	c.1655C>T	p.Ala552Val	missense_variant	Exon 16 of 20	1	NM_057169.5	ENSP00000347464.3		Q14161-1

Frequencies

GnomAD3 genomes

AF:

0.0517

AC:

7868

AN:

152104

Hom.:

293

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0941

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.0297

Gnomad ASJ

AF:

0.0124

Gnomad EAS

AF:

0.112

Gnomad SAS

AF:

0.0365

Gnomad FIN

AF:

0.0364

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0325

Gnomad OTH

AF:

0.0489

GnomAD2 exomes

AF:

0.0397

AC:

9836

AN:

247792

AF XY:

0.0384

show subpopulations

Gnomad AFR exome

AF:

0.0969

Gnomad AMR exome

AF:

0.0219

Gnomad ASJ exome

AF:

0.0140

Gnomad EAS exome

AF:

0.108

Gnomad FIN exome

AF:

0.0348

Gnomad NFE exome

AF:

0.0313

Gnomad OTH exome

AF:

0.0361

GnomAD4 exome

AF:

0.0329

AC:

45353

AN:

1377754

Hom.:

968

Cov.:

AF XY:

0.0328

AC XY:

22631

AN XY:

689706

show subpopulations

African (AFR)

AF:

0.0955

AC:

3021

AN:

31632

American (AMR)

AF:

0.0227

AC:

1007

AN:

44430

Ashkenazi Jewish (ASJ)

AF:

0.0130

AC:

334

AN:

25602

East Asian (EAS)

AF:

0.0887

AC:

3477

AN:

39180

South Asian (SAS)

AF:

0.0326

AC:

2746

AN:

84260

European-Finnish (FIN)

AF:

0.0332

AC:

1771

AN:

53312

Middle Eastern (MID)

AF:

0.0522

AC:

295

AN:

5646

European-Non Finnish (NFE)

AF:

0.0295

AC:

30575

AN:

1036266

Other (OTH)

AF:

0.0370

AC:

2127

AN:

57426

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

1847

3694

5541

7388

9235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1146

2292

3438

4584

5730

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0517

AC:

7874

AN:

152222

Hom.:

293

Cov.:

AF XY:

0.0520

AC XY:

3867

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0939

AC:

3896

AN:

41496

American (AMR)

AF:

0.0296

AC:

453

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0124

AC:

AN:

3470

East Asian (EAS)

AF:

0.112

AC:

581

AN:

5180

South Asian (SAS)

AF:

0.0373

AC:

180

AN:

4824

European-Finnish (FIN)

AF:

0.0364

AC:

386

AN:

10610

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0325

AC:

2213

AN:

68030

Other (OTH)

AF:

0.0488

AC:

103

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

383

766

1150

1533

1916

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0391

Hom.:

687

Bravo

AF:

0.0543

TwinsUK

AF:

0.0307

AC:

114

ALSPAC

AF:

0.0381

AC:

147

ESP6500AA

AF:

0.0969

AC:

427

ESP6500EA

AF:

0.0312

AC:

268

ExAC

AF:

0.0410

AC:

4976

Asia WGS

AF:

0.0880

AC:

307

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 13, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29874175) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.052

T;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

D;D

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.4

L;.

PhyloP100

7.7

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.21

Sift

Benign

0.25

T;T

Sift4G

Benign

0.25

T;T

Polyphen

0.85

P;.

Vest4

0.18

MPC

0.49

ClinPred

0.022

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.34

Mutation Taster

=74/26

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over