chr2-9374758-T-G

Variant names:

• chr2-9374758-T-G
• rs748276692
• NM_003887.3:c.1560T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003887.3(ASAP2):​c.1560T>G​(p.Asn520Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASAP2 NM_003887.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.678
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003887.3. 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
	ASAP2	NM_003887.3	MANE Select	c.1560T>G	p.Asn520Lys	missense	Exon 17 of 28	NP_003878.1	O43150-1
	ASAP2	NM_001135191.2		c.1560T>G	p.Asn520Lys	missense	Exon 17 of 27	NP_001128663.1	O43150-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAP2	ENST00000281419.8	TSL:1 MANE Select	c.1560T>G	p.Asn520Lys	missense	Exon 17 of 28	ENSP00000281419.3	O43150-1
	ASAP2	ENST00000315273.4	TSL:1	c.1560T>G	p.Asn520Lys	missense	Exon 17 of 27	ENSP00000316404.4	O43150-2
	ASAP2	ENST00000865541.1		c.1593T>G	p.Asn531Lys	missense	Exon 17 of 28	ENSP00000535600.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0084	T
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.68
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.070
Sift	Benign	0.70	T
Sift4G	Benign	0.57	T
Polyphen		0.012	B
Vest4		0.77
MutPred		0.60		Gain of MoRF binding (P = 0.043)
MVP		0.32
MPC		0.27
ClinPred		0.59	D
GERP RS		-1.6
Varity_R		0.10
gMVP		0.23
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.38		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs748276692; hg19: chr2-9514887;