Variant 7-26725472-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003930.5(SKAP2):c.752C>T(p.Thr251Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,459,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SKAP2
NM_003930.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.243

Variant links:

Genes affected

SKAP2 (HGNC:15687): (src kinase associated phosphoprotein 2) The protein encoded by this gene shares homology with Src kinase-associated phosphoprotein 1, and is a substrate of Src family kinases. It is an adaptor protein that is thought to play an essential role in the Src signaling pathway, and in regulating proper activation of the immune system. This protein contains an amino terminal coiled-coil domain for self-dimerization, a plecskstrin homology (PH) domain required for interactions with lipids at the membrane, and a Src homology (SH3) domain at the carboxy terminus. Some reports indicate that this protein inhibits actin polymerization through interactions with actin assembly factors, and might negatively regulate the invasiveness of tumors by modulating actin assembly. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2015]

SKAP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06075743).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SKAP2	NM_003930.5 linkuse as main transcript	c.752C>T	p.Thr251Ile	missense_variant	9/13	ENST00000345317.7
SKAP2	NM_001303468.2 linkuse as main transcript	c.236C>T	p.Thr79Ile	missense_variant	9/13
SKAP2	XM_017012771.3 linkuse as main transcript	c.752C>T	p.Thr251Ile	missense_variant	9/13
SKAP2	XM_047421010.1 linkuse as main transcript	c.236C>T	p.Thr79Ile	missense_variant	6/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SKAP2	ENST00000345317.7 linkuse as main transcript	c.752C>T	p.Thr251Ile	missense_variant	9/13	1	NM_003930.5	P1
SKAP2	ENST00000489977.5 linkuse as main transcript	n.579C>T		non_coding_transcript_exon_variant	6/7	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1459954

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726342

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

The c.752C>T (p.T251I) alteration is located in exon 9 (coding exon 9) of the SKAP2 gene. This alteration results from a C to T substitution at nucleotide position 752, causing the threonine (T) at amino acid position 251 to be replaced by an isoleucine (I). 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

0.078

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.74

CADD

Benign

2.4

DANN

Benign

0.83

DEOGEN2

Benign

0.12

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.38

M_CAP

Benign

0.0050

MetaRNN

Benign

0.061

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.7

REVEL

Benign

0.012

Sift

Benign

0.17

Sift4G

Benign

0.16

Polyphen

0.0

Vest4

0.032

MutPred

0.19

Loss of phosphorylation at T251 (P = 0.0132);

MVP

0.12

MPC

0.24

ClinPred

0.052

GERP RS

-0.52

Varity_R

0.041

gMVP

0.23

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over