17-30922060-C-G

Variant names:

• chr17-30922060-C-G
• rs1484476611
• NM_018404.3:c.46C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018404.3(ADAP2):​c.46C>G​(p.Arg16Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000892 in 1,120,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.9e-7 (0 hom.)
• Consequence: ADAP2 NM_018404.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0750

Genes affected

ADAP2 (HGNC:16487): (ArfGAP with dual PH domains 2) The protein encoded by this gene binds beta-tubulin and increases the stability of microtubules. The encoded protein can also translocate to the cell membrane and bind phosphatidylinositol 3,4,5-trisphosphate (PtdInsP3) and inositol 1,3,4,5-tetrakisphosphate (InsP4). In addition, this protein is a GTPase-activating protein for ADP ribosylation factor 6 and may be able to block the entry of some RNA viruses. [provided by RefSeq, Oct 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32966095).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAP2	NM_018404.3	c.46C>G	p.Arg16Gly	missense_variant	Exon 1 of 11	ENST00000330889.8	NP_060874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAP2	ENST00000330889.8	c.46C>G	p.Arg16Gly	missense_variant	Exon 1 of 11	1	NM_018404.3	ENSP00000329468.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.92e-7 AC: 1 AN: 1120932 Hom.: 0 Cov.: 31 AF XY: 0.00000186 AC XY: 1 AN XY: 539036

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000379

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.46C>G (p.R16G) alteration is located in exon 1 (coding exon 1) of the ADAP2 gene. This alteration results from a C to G substitution at nucleotide position 46, causing the arginine (R) at amino acid position 16 to be replaced by a glycine (G). 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	0.11
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.20	T;T;.
Eigen	Benign	-0.042
Eigen_PC	Benign	0.052
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.53	T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.6	L;.;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-2.2	N;.;.
REVEL	Benign	0.15
Sift	Benign	0.037	D;.;.
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.12	B;B;.
Vest4		0.14
MutPred		0.70		Loss of MoRF binding (P = 0.0376);Loss of MoRF binding (P = 0.0376);Loss of MoRF binding (P = 0.0376);
MVP		0.39
MPC		0.57
ClinPred		0.55	D
GERP RS		3.8
Varity_R		0.28
gMVP		0.26

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

Publications

LitVar

Other links and lift over

dbSNP: rs1484476611; hg19: chr17-29249078;