12-109959858-G-A

Variant names:

• chr12-109959858-G-A
• rs763631836
• NM_057169.5:c.1088C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_057169.5(GIT2):​c.1088C>T​(p.Ser363Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000997 in 1,605,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: GIT2 NM_057169.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.08
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14843306).

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.1088C>T	p.Ser363Leu	missense	Exon 12 of 20	NP_476510.1	Q14161-1
	GIT2	NM_001135214.3		c.1088C>T	p.Ser363Leu	missense	Exon 12 of 19	NP_001128686.1	Q14161-5
	GIT2	NM_001330153.2		c.1085C>T	p.Ser362Leu	missense	Exon 12 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.1088C>T	p.Ser363Leu	missense	Exon 12 of 20	ENSP00000347464.3	Q14161-1
	GIT2	ENST00000457474.6	TSL:1	c.1094C>T	p.Ser365Leu	missense	Exon 13 of 19	ENSP00000391813.2	Q14161-10
	GIT2	ENST00000547815.5	TSL:1	c.1088C>T	p.Ser363Leu	missense	Exon 12 of 15	ENSP00000450348.1	Q14161-2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251138 AF XY: 0.00000737

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000895 AC: 13 AN: 1453140 Hom.: 0 Cov.: 28 AF XY: 0.00000968 AC XY: 7 AN XY: 723384

African (AFR) AF: 0.0000601 AC: 2 AN: 33272

American (AMR) AF: 0.0000448 AC: 2 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86046

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000725 AC: 8 AN: 1104132

Other (OTH) AF: 0.00 AC: 0 AN: 60088

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74290

African (AFR) AF: 0.0000241 AC: 1 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68036

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

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.00000824 AC: 1

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	0.064
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.1
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.054
Sift	Benign	0.12	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.35		Gain of catalytic residue at K366 (P = 0.0044)
MVP		0.56
MPC		0.44
ClinPred		0.37	T
GERP RS		3.5
Varity_R		0.094
gMVP		0.16
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs763631836; hg19: chr12-110397663; COSMIC: COSV100188918; COSMIC: COSV100188918;