7-26864395-G-A

Position:

• chr7-26864395-G-A

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.35C>T​(p.Pro12Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00449 in 1,612,938 control chromosomes in the GnomAD database, including 267 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.024 (141 hom., cov: 31)
  • Exomes 𝑓: 0.0025 (126 hom.)
• Consequence: SKAP2 NM_003930.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.45

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=0.0016732216).
• BP6: Variant 7-26864395-G-A is Benign according to our data. Variant chr7-26864395-G-A is described in ClinVar as [Benign]. Clinvar id is 776212.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0795 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SKAP2	NM_003930.5	c.35C>T	p.Pro12Leu	missense_variant	1/13	ENST00000345317.7
SKAP2	XM_017012771.3	c.35C>T	p.Pro12Leu	missense_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SKAP2	ENST00000345317.7	c.35C>T	p.Pro12Leu	missense_variant	1/13	1	NM_003930.5	P1

Frequencies

GnomAD3 genomes AF: 0.0236 AC: 3589 AN: 152064 Hom.: 142 Cov.: 31

Gnomad AFR AF: 0.0819

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00943

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.00663 AC: 1650 AN: 248726 Hom.: 62 AF XY: 0.00494 AC XY: 664 AN XY: 134534

Gnomad AFR exome AF: 0.0836

Gnomad AMR exome AF: 0.00740

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000215

Gnomad OTH exome AF: 0.00330

GnomAD4 exome AF: 0.00250 AC: 3648 AN: 1460756 Hom.: 126 Cov.: 31 AF XY: 0.00209 AC XY: 1520 AN XY: 726714

Gnomad4 AFR exome AF: 0.0811

Gnomad4 AMR exome AF: 0.00838

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000220

Gnomad4 OTH exome AF: 0.00501

GnomAD4 genome AF: 0.0236 AC: 3593 AN: 152182 Hom.: 141 Cov.: 31 AF XY: 0.0227 AC XY: 1692 AN XY: 74420

Gnomad4 AFR AF: 0.0818

Gnomad4 AMR AF: 0.00942

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.00410 Hom.: 24

Bravo AF: 0.0275

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0819 AC: 361

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00773 AC: 938

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000417

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

Labcorp Genetics (formerly Invitae), Labcorp

Jun 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Benign	0.081	T
Eigen	Benign	0.076
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.67	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.055
Sift	Benign	0.16	T
Sift4G	Benign	0.27	T
Polyphen		0.19	B
Vest4		0.17
MVP		0.28
MPC		0.23
ClinPred		0.062	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.4
Varity_R		0.21
gMVP		0.18

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: rs137938529; hg19: chr7-26904014;