2-9356320-C-T

Position:

• chr2-9356320-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003887.3(ASAP2):​c.1302C>T​(p.Asp434=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00354 in 1,606,026 control chromosomes in the GnomAD database, including 144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (81 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (63 hom.)
• Consequence: ASAP2 NM_003887.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.690

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 2-9356320-C-T is Benign according to our data. Variant chr2-9356320-C-T is described in ClinVar as [Benign]. Clinvar id is 767783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.69 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASAP2	NM_003887.3	c.1302C>T	p.Asp434=	synonymous_variant	14/28	ENST00000281419.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASAP2	ENST00000281419.8	c.1302C>T	p.Asp434=	synonymous_variant	14/28	1	NM_003887.3	P3
ASAP2	ENST00000315273.4	c.1302C>T	p.Asp434=	synonymous_variant	14/27	1		A1
ASAP2	ENST00000641030.1	c.843C>T	p.Asp281=	synonymous_variant	10/11
ASAP2	ENST00000471687.1			downstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 2822 AN: 152172 Hom.: 81 Cov.: 32

Gnomad AFR AF: 0.0639

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00753

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00514 AC: 1249 AN: 243036 Hom.: 22 AF XY: 0.00389 AC XY: 509 AN XY: 130924

Gnomad AFR exome AF: 0.0659

Gnomad AMR exome AF: 0.00332

Gnomad ASJ exome AF: 0.00235

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000453

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000173

Gnomad OTH exome AF: 0.00306

GnomAD4 exome AF: 0.00197 AC: 2864 AN: 1453736 Hom.: 63 Cov.: 33 AF XY: 0.00174 AC XY: 1258 AN XY: 722546

Gnomad4 AFR exome AF: 0.0665

Gnomad4 AMR exome AF: 0.00344

Gnomad4 ASJ exome AF: 0.00168

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000366

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000123

Gnomad4 OTH exome AF: 0.00468

GnomAD4 genome AF: 0.0186 AC: 2828 AN: 152290 Hom.: 81 Cov.: 32 AF XY: 0.0180 AC XY: 1343 AN XY: 74480

Gnomad4 AFR AF: 0.0639

Gnomad4 AMR AF: 0.00752

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.0104 Hom.: 35

Bravo AF: 0.0217

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 08, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	1.8
DANN	Benign	0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34052263; hg19: chr2-9496449;