7-26725466-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003930.5(SKAP2):c.758G>C(p.Ser253Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00303 in 1,611,884 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.016 (62 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (56 hom.)
• Consequence: SKAP2 NM_003930.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.311

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023711324).
• BP6: Variant 7-26725466-C-G is Benign according to our data. Variant chr7-26725466-C-G is described in ClinVar as [Benign]. Clinvar id is 789007.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SKAP2	NM_003930.5	c.758G>C	p.Ser253Thr	missense_variant	9/13	ENST00000345317.7
SKAP2	NM_001303468.2	c.242G>C	p.Ser81Thr	missense_variant	9/13
SKAP2	XM_017012771.3	c.758G>C	p.Ser253Thr	missense_variant	9/13
SKAP2	XM_047421010.1	c.242G>C	p.Ser81Thr	missense_variant	6/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SKAP2	ENST00000345317.7	c.758G>C	p.Ser253Thr	missense_variant	9/13	1	NM_003930.5	P1
SKAP2	ENST00000489977.5	n.585G>C		non_coding_transcript_exon_variant	6/7	5

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2418 AN: 151944 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.0552

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00715

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00719

GnomAD3 exomes AF: 0.00430 AC: 1074 AN: 249626 Hom.: 25 AF XY: 0.00310 AC XY: 419 AN XY: 135002

Gnomad AFR exome AF: 0.0581

Gnomad AMR exome AF: 0.00276

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000987

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.00168 AC: 2459 AN: 1459822 Hom.: 56 Cov.: 31 AF XY: 0.00142 AC XY: 1029 AN XY: 726268

Gnomad4 AFR exome AF: 0.0566

Gnomad4 AMR exome AF: 0.00332

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000151

Gnomad4 OTH exome AF: 0.00366

GnomAD4 genome AF: 0.0159 AC: 2420 AN: 152062 Hom.: 62 Cov.: 32 AF XY: 0.0155 AC XY: 1150 AN XY: 74346

Gnomad4 AFR AF: 0.0551

Gnomad4 AMR AF: 0.00714

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00712

Alfa AF: 0.00127 Hom.: 2

Bravo AF: 0.0183

ESP6500AA AF: 0.0570 AC: 251

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00507 AC: 616

Asia WGS AF: 0.00202 AC: 7 AN: 3476

EpiCase AF: 0.000437

EpiControl AF: 0.000297

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	6.3
Dann	Benign	0.70
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.10
Sift	Benign	0.28	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.047
MVP		0.31
MPC		0.20
ClinPred		0.00059	T
GERP RS		0.86
Varity_R		0.060
gMVP		0.16

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: rs17154402; hg19: chr7-26765085;