rs11068997

Positions:

• chr12-109945336-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000355312.8(GIT2):​c.1655C>T​(p.Ala552Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0348 in 1,529,976 control chromosomes in the GnomAD database, including 1,261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.052 (293 hom., cov: 32)
  • Exomes 𝑓: 0.033 (968 hom.)
• Consequence: GIT2 ENST00000355312.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.69

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015673637).
• BP6: Variant 12-109945336-G-A is Benign according to our data. Variant chr12-109945336-G-A is described in ClinVar as [Benign]. Clinvar id is 1276394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GIT2	NM_057169.5	c.1655C>T	p.Ala552Val	missense_variant	16/20	ENST00000355312.8	NP_476510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GIT2	ENST00000355312.8	c.1655C>T	p.Ala552Val	missense_variant	16/20	1	NM_057169.5	ENSP00000347464	P3

Frequencies

GnomAD3 genomes AF: 0.0517 AC: 7868 AN: 152104 Hom.: 293 Cov.: 32

Gnomad AFR AF: 0.0941

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0297

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.0365

Gnomad FIN AF: 0.0364

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0325

Gnomad OTH AF: 0.0489

GnomAD3 exomes AF: 0.0397 AC: 9836 AN: 247792 Hom.: 315 AF XY: 0.0384 AC XY: 5144 AN XY: 133996

Gnomad AFR exome AF: 0.0969

Gnomad AMR exome AF: 0.0219

Gnomad ASJ exome AF: 0.0140

Gnomad EAS exome AF: 0.108

Gnomad SAS exome AF: 0.0325

Gnomad FIN exome AF: 0.0348

Gnomad NFE exome AF: 0.0313

Gnomad OTH exome AF: 0.0361

GnomAD4 exome AF: 0.0329 AC: 45353 AN: 1377754 Hom.: 968 Cov.: 23 AF XY: 0.0328 AC XY: 22631 AN XY: 689706

Gnomad4 AFR exome AF: 0.0955

Gnomad4 AMR exome AF: 0.0227

Gnomad4 ASJ exome AF: 0.0130

Gnomad4 EAS exome AF: 0.0887

Gnomad4 SAS exome AF: 0.0326

Gnomad4 FIN exome AF: 0.0332

Gnomad4 NFE exome AF: 0.0295

Gnomad4 OTH exome AF: 0.0370

GnomAD4 genome AF: 0.0517 AC: 7874 AN: 152222 Hom.: 293 Cov.: 32 AF XY: 0.0520 AC XY: 3867 AN XY: 74436

Gnomad4 AFR AF: 0.0939

Gnomad4 AMR AF: 0.0296

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.112

Gnomad4 SAS AF: 0.0373

Gnomad4 FIN AF: 0.0364

Gnomad4 NFE AF: 0.0325

Gnomad4 OTH AF: 0.0488

Alfa AF: 0.0370 Hom.: 291

Bravo AF: 0.0543

TwinsUK AF: 0.0307 AC: 114

ALSPAC AF: 0.0381 AC: 147

ESP6500AA AF: 0.0969 AC: 427

ESP6500EA AF: 0.0312 AC: 268

ExAC AF: 0.0410 AC: 4976

Asia WGS AF: 0.0880 AC: 307 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2018	This variant is associated with the following publications: (PMID: 29874175) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.052	T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	0.0000012	P;P;P;P;P;P;P;P;P;P
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.21
Sift	Benign	0.25	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.85	P;.
Vest4		0.18
MPC		0.49
ClinPred		0.022	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs11068997; hg19: chr12-110383141;