2-9374865-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003887.3(ASAP2):c.1667C>T(p.Thr556Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,613,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: ASAP2 NM_003887.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.61

Genes affected

ASAP2 (HGNC:2721): (ArfGAP with SH3 domain, ankyrin repeat and PH domain 2) This gene encodes a multidomain protein containing an N-terminal alpha-helical region with a coiled-coil motif, followed by a pleckstrin homology (PH) domain, an Arf-GAP domain, an ankyrin homology region, a proline-rich region, and a C-terminal Src homology 3 (SH3) domain. The protein localizes in the Golgi apparatus and at the plasma membrane, where it colocalizes with protein tyrosine kinase 2-beta (PYK2). The encoded protein forms a stable complex with PYK2 in vivo. This interaction appears to be mediated by binding of its SH3 domain to the C-terminal proline-rich domain of PYK2. The encoded protein is tyrosine phosphorylated by activated PYK2. It has catalytic activity for class I and II ArfGAPs in vitro, and can bind the class III Arf ARF6 without immediate GAP activity. The encoded protein is believed to function as an ARF GAP that controls ARF-mediated vesicle budding when recruited to Golgi membranes. In addition, it functions as a substrate and downstream target for PYK2 and SRC, a pathway that may be involved in the regulation of vesicular transport. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21272081).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASAP2	NM_003887.3	c.1667C>T	p.Thr556Met	missense_variant	17/28	ENST00000281419.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASAP2	ENST00000281419.8	c.1667C>T	p.Thr556Met	missense_variant	17/28	1	NM_003887.3	P3
ASAP2	ENST00000315273.4	c.1667C>T	p.Thr556Met	missense_variant	17/27	1		A1

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151804 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000969

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251416 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135886

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461826 Hom.: 0 Cov.: 33 AF XY: 0.0000220 AC XY: 16 AN XY: 727216

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151804 Hom.: 0 Cov.: 31 AF XY: 0.0000675 AC XY: 5 AN XY: 74084

Gnomad4 AFR AF: 0.0000969

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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

Sep 16, 2021

The c.1667C>T (p.T556M) alteration is located in exon 17 (coding exon 17) of the ASAP2 gene. This alteration results from a C to T substitution at nucleotide position 1667, causing the threonine (T) at amino acid position 556 to be replaced by a methionine (M). 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	0.073
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	0.58	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.10
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.10	T;T
Polyphen		0.97	D;D
Vest4		0.34
MutPred		0.42		Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);
MVP		0.44
MPC		0.19
ClinPred		0.10	T
GERP RS		4.4
Varity_R		0.089
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: rs752933805; hg19: chr2-9514994; COSMIC: COSV55637914;