chr12-109933156-C-T

Variant names:

• chr12-109933156-C-T
• rs753666949
• NM_057169.5:c.2102G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_057169.5(GIT2):​c.2102G>A​(p.Arg701His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000468 in 1,581,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: GIT2 NM_057169.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91
• Publications: 4 publications found

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

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37204933).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_057169.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIT2	NM_057169.5	MANE Select	c.2102G>A	p.Arg701His	missense	Exon 20 of 20	NP_476510.1	Q14161-1
	GIT2	NM_001135214.3		c.2012G>A	p.Arg671His	missense	Exon 19 of 19	NP_001128686.1	Q14161-5
	GIT2	NM_001330153.2		c.1949G>A	p.Arg650His	missense	Exon 19 of 19	NP_001317082.1	F8VXI9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIT2	ENST00000355312.8	TSL:1 MANE Select	c.2102G>A	p.Arg701His	missense	Exon 20 of 20	ENSP00000347464.3	Q14161-1
	GIT2	ENST00000457474.6	TSL:1	c.1868G>A	p.Arg623His	missense	Exon 19 of 19	ENSP00000391813.2	Q14161-10
	GIT2	ENST00000876497.1		c.2099G>A	p.Arg700His	missense	Exon 20 of 20	ENSP00000546556.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000466 AC: 9 AN: 193292 AF XY: 0.0000677

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000215

Gnomad FIN exome AF: 0.0000530

Gnomad NFE exome AF: 0.0000246

Gnomad OTH exome AF: 0.000195

GnomAD4 exome AF: 0.0000476 AC: 68 AN: 1428836 Hom.: 0 Cov.: 29 AF XY: 0.0000480 AC XY: 34 AN XY: 708010

African (AFR) AF: 0.00 AC: 0 AN: 32762

American (AMR) AF: 0.0000260 AC: 1 AN: 38456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25548

East Asian (EAS) AF: 0.000262 AC: 10 AN: 38168

South Asian (SAS) AF: 0.0000241 AC: 2 AN: 82984

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51702

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.0000475 AC: 52 AN: 1094262

Other (OTH) AF: 0.0000338 AC: 2 AN: 59236

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152168 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000335 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.022	D
MutationAssessor	Benign	1.8	L
PhyloP100		7.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.078	T
Polyphen		0.21	B
Vest4		0.54
MutPred		0.35		Gain of catalytic residue at L703 (P = 0.0015)
MVP		0.89
MPC		0.98
ClinPred		0.26	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.47
Mutation Taster		=37/63	disease causing

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

Other links and lift over

dbSNP: rs753666949; hg19: chr12-110370961; COSMIC: COSV58079427; COSMIC: COSV58079427;