NM_057169.5:c.1522C>T

Variant names:

• chr12-109947375-G-A
• rs376799498
• NM_057169.5:c.1522C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_057169.5(GIT2):​c.1522C>T​(p.Arg508Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GIT2 NM_057169.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.11
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.79

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.1522C>T	p.Arg508Trp	missense	Exon 15 of 20	NP_476510.1	Q14161-1
	GIT2	NM_001135214.3		c.1522C>T	p.Arg508Trp	missense	Exon 15 of 19	NP_001128686.1	Q14161-5
	GIT2	NM_001330153.2		c.1369C>T	p.Arg457Trp	missense	Exon 14 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.1522C>T	p.Arg508Trp	missense	Exon 15 of 20	ENSP00000347464.3	Q14161-1
	GIT2	ENST00000457474.6	TSL:1	c.1378C>T	p.Arg460Trp	missense	Exon 15 of 19	ENSP00000391813.2	Q14161-10
	GIT2	ENST00000547815.5	TSL:1	c.*1448C>T		3_prime_UTR	Exon 15 of 15	ENSP00000450348.1	Q14161-2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251462 AF XY: 0.00000736

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461846 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727218

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74344

African (AFR) AF: 0.0000724 AC: 3 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

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

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000340

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

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	0.29
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.8	L
PhyloP100		9.1
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.74
MVP		0.76
MPC		1.4
ClinPred		0.99	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.46
gMVP		0.57
Mutation Taster		=24/76	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: rs376799498; hg19: chr12-110385180;