12-109934057-C-T

Variant summary

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

The NM_057169.5(GIT2):c.2032G>A(p.Val678Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 1,572,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: GIT2 NM_057169.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.743

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.022691518).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GIT2	NM_057169.5	c.2032G>A	p.Val678Ile	missense_variant	19/20	ENST00000355312.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GIT2	ENST00000355312.8	c.2032G>A	p.Val678Ile	missense_variant	19/20	1	NM_057169.5	P3

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000183 AC: 46 AN: 251478 Hom.: 0 AF XY: 0.000206 AC XY: 28 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000281

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000216 AC: 307 AN: 1420404 Hom.: 0 Cov.: 24 AF XY: 0.000202 AC XY: 143 AN XY: 708930

Gnomad4 AFR exome AF: 0.0000308

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000252

Gnomad4 OTH exome AF: 0.000220

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74484

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000260 Hom.: 0

Bravo AF: 0.000178

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2021

The c.2032G>A (p.V678I) alteration is located in exon 19 (coding exon 19) of the GIT2 gene. This alteration results from a G to A substitution at nucleotide position 2032, causing the valine (V) at amino acid position 678 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	12
Dann	Benign	0.97
DEOGEN2	Benign	0.087	T;T;.;.;.;.;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.68	T;T;T;T;T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.023	T;T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.4	L;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.16	N;N;N;N;N;N;.
REVEL	Benign	0.087
Sift	Benign	0.071	T;T;T;T;T;T;.
Sift4G	Benign	0.37	T;T;T;T;T;T;.
Polyphen		0.28	B;B;B;B;P;.;.
Vest4		0.12
MVP		0.49
MPC		0.40
ClinPred		0.032	T
GERP RS		2.9
Varity_R		0.024
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs146384144; hg19: chr12-110371862; COSMIC: COSV100618957; COSMIC: COSV100618957;