12-109959933-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_057169.5(GIT2):c.1013A>G(p.Asn338Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00061 in 1,613,430 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (0 hom.)
• Consequence: GIT2 NM_057169.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.21

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]

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.012105256).
• BP6: Variant 12-109959933-T-C is Benign according to our data. Variant chr12-109959933-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 776750.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GIT2	NM_057169.5	c.1013A>G	p.Asn338Ser	missense_variant	12/20	ENST00000355312.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GIT2	ENST00000355312.8	c.1013A>G	p.Asn338Ser	missense_variant	12/20	1	NM_057169.5	P3

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 152060 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000685 AC: 172 AN: 251266 Hom.: 0 AF XY: 0.000619 AC XY: 84 AN XY: 135810

Gnomad AFR exome AF: 0.00369

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000882

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000484

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000524 AC: 766 AN: 1461252 Hom.: 0 Cov.: 29 AF XY: 0.000534 AC XY: 388 AN XY: 726992

Gnomad4 AFR exome AF: 0.00385

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00165

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00122

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000411

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.00143 AC: 218 AN: 152178 Hom.: 1 Cov.: 32 AF XY: 0.00133 AC XY: 99 AN XY: 74406

Gnomad4 AFR AF: 0.00385

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00146

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000859 Hom.: 2

Bravo AF: 0.00145

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000700 AC: 85

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.31	T;T;.;.;.;.;T;.;T
Eigen	Benign	0.036
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.012	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;.;.;N;N;.;.;N;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.8	D;D;D;D;N;D;.;D;D
REVEL	Benign	0.059
Sift	Benign	0.17	T;T;T;T;T;T;.;T;T
Sift4G	Benign	0.30	T;T;T;T;T;T;.;T;T
Polyphen		0.040	B;B;B;B;B;.;.;.;.
Vest4		0.44
MVP		0.44
MPC		0.51
ClinPred		0.031	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs9804905; hg19: chr12-110397738;