NM_057169.5:c.1655C>T

Variant names:

• chr12-109945336-G-A
• rs11068997
• NM_057169.5:c.1655C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_057169.5(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 (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (293 hom., cov: 32)
  • Exomes 𝑓: 0.033 (968 hom.)
• Consequence: GIT2 NM_057169.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.69
• Publications: 15 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: Benign. The variant received -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 VariationId 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.

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.1655C>T	p.Ala552Val	missense	Exon 16 of 20	NP_476510.1	Q14161-1
	GIT2	NM_001330153.2		c.1502C>T	p.Ala501Val	missense	Exon 15 of 19	NP_001317082.1	F8VXI9
	GIT2	NM_001135214.3		c.1641+1920C>T		intron	N/A	NP_001128686.1	Q14161-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GIT2	ENST00000355312.8	TSL:1 MANE Select	c.1655C>T	p.Ala552Val	missense	Exon 16 of 20	ENSP00000347464.3	Q14161-1
	GIT2	ENST00000457474.6	TSL:1	c.1497+1920C>T		intron	N/A	ENSP00000391813.2	Q14161-10
	GIT2	ENST00000876497.1		c.1652C>T	p.Ala551Val	missense	Exon 16 of 20	ENSP00000546556.1

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

GnomAD2 exomes AF: 0.0397 AC: 9836 AN: 247792 AF XY: 0.0384

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 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

African (AFR) AF: 0.0955 AC: 3021 AN: 31632

American (AMR) AF: 0.0227 AC: 1007 AN: 44430

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 334 AN: 25602

East Asian (EAS) AF: 0.0887 AC: 3477 AN: 39180

South Asian (SAS) AF: 0.0326 AC: 2746 AN: 84260

European-Finnish (FIN) AF: 0.0332 AC: 1771 AN: 53312

Middle Eastern (MID) AF: 0.0522 AC: 295 AN: 5646

European-Non Finnish (NFE) AF: 0.0295 AC: 30575 AN: 1036266

Other (OTH) AF: 0.0370 AC: 2127 AN: 57426

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

African (AFR) AF: 0.0939 AC: 3896 AN: 41496

American (AMR) AF: 0.0296 AC: 453 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 43 AN: 3470

East Asian (EAS) AF: 0.112 AC: 581 AN: 5180

South Asian (SAS) AF: 0.0373 AC: 180 AN: 4824

European-Finnish (FIN) AF: 0.0364 AC: 386 AN: 10610

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0325 AC: 2213 AN: 68030

Other (OTH) AF: 0.0488 AC: 103 AN: 2110

Alfa AF: 0.0391 Hom.: 687

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L
PhyloP100		7.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.21
Sift	Benign	0.25	T
Sift4G	Benign	0.25	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
Mutation Taster		=74/26	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11068997; hg19: chr12-110383141; COSMIC: COSV107330651; COSMIC: COSV107330651;