12-109953098-C-T

Variant names:

• chr12-109953098-C-T
• rs112819417
• NM_057169.5:c.1236G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_057169.5(GIT2):​c.1236G>A​(p.Arg412Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000543 in 1,614,154 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (2 hom.)
• Consequence: GIT2 NM_057169.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0610
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 12-109953098-C-T is Benign according to our data. Variant chr12-109953098-C-T is described in ClinVar as Benign. ClinVar VariationId is 785425.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.061 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 gene

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.1236G>A	p.Arg412Arg	synonymous	Exon 13 of 20	NP_476510.1	Q14161-1
	GIT2	NM_001135214.3		c.1236G>A	p.Arg412Arg	synonymous	Exon 13 of 19	NP_001128686.1	Q14161-5
	GIT2	NM_001330153.2		c.1233G>A	p.Arg411Arg	synonymous	Exon 13 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.1236G>A	p.Arg412Arg	synonymous	Exon 13 of 20	ENSP00000347464.3	Q14161-1
	GIT2	ENST00000457474.6	TSL:1	c.1242G>A	p.Arg414Arg	synonymous	Exon 14 of 19	ENSP00000391813.2	Q14161-10
	GIT2	ENST00000547815.5	TSL:1	c.1236G>A	p.Arg412Arg	synonymous	Exon 13 of 15	ENSP00000450348.1	Q14161-2

Frequencies

GnomAD3 genomes AF: 0.00292 AC: 444 AN: 152210 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

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: 0.0000294

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000660 AC: 166 AN: 251386 AF XY: 0.000508

Gnomad AFR exome AF: 0.00843

Gnomad AMR exome AF: 0.000723

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: 0.000652

GnomAD4 exome AF: 0.000292 AC: 427 AN: 1461826 Hom.: 2 Cov.: 31 AF XY: 0.000259 AC XY: 188 AN XY: 727206

African (AFR) AF: 0.0106 AC: 356 AN: 33480

American (AMR) AF: 0.000827 AC: 37 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

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: 5736

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111986

Other (OTH) AF: 0.000530 AC: 32 AN: 60390

GnomAD4 genome AF: 0.00295 AC: 450 AN: 152328 Hom.: 2 Cov.: 32 AF XY: 0.00290 AC XY: 216 AN XY: 74514

African (AFR) AF: 0.0102 AC: 425 AN: 41572

American (AMR) AF: 0.00137 AC: 21 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68036

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.00310

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	11
DANN	Benign	0.89
PhyloP100		-0.061
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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: rs112819417; hg19: chr12-110390903;