12-109959858-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_057169.5(GIT2):​c.1088C>G​(p.Ser363Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S363L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GIT2 NM_057169.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.08
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37623054).

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>G	p.Ser363Trp	missense	Exon 12 of 20	NP_476510.1	Q14161-1
	GIT2	NM_001135214.3		c.1088C>G	p.Ser363Trp	missense	Exon 12 of 19	NP_001128686.1	Q14161-5
	GIT2	NM_001330153.2		c.1085C>G	p.Ser362Trp	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>G	p.Ser363Trp	missense	Exon 12 of 20	ENSP00000347464.3	Q14161-1
	GIT2	ENST00000457474.6	TSL:1	c.1094C>G	p.Ser365Trp	missense	Exon 13 of 19	ENSP00000391813.2	Q14161-10
	GIT2	ENST00000547815.5	TSL:1	c.1088C>G	p.Ser363Trp	missense	Exon 12 of 15	ENSP00000450348.1	Q14161-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453140 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 723384

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33272

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 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: 9.06e-7 AC: 1 AN: 1104132

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.1
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.015	D
Polyphen		0.90	P
Vest4		0.42
MutPred		0.41		Loss of disorder (P = 0.0037)
MVP		0.73
MPC		0.97
ClinPred		0.90	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.29
Mutation Taster		=85/15	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;