Genetic Variant SYK:p.Ile262Leu (chr9-90864655-A-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003177.7(SYK):c.784A>C(p.Ile262Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,614,124 control chromosomes in the GnomAD database, including 25 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0061 ( 12 hom., cov: 33)

Exomes 𝑓: 0.00081 ( 13 hom. )

Consequence

SYK
NM_003177.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.08

Publications

7 publications found

Variant links:

Genes affected

SYK (HGNC:11491): (spleen associated tyrosine kinase) This gene encodes a member of the family of non-receptor type Tyr protein kinases. This protein is widely expressed in hematopoietic cells and is involved in coupling activated immunoreceptors to downstream signaling events that mediate diverse cellular responses, including proliferation, differentiation, and phagocytosis. It is thought to be a modulator of epithelial cell growth and a potential tumour suppressor in human breast carcinomas. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

SYK Gene-Disease associations (from GenCC):

immunodeficiency 82 with systemic inflammation
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia

SYK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0060960352).

BP6

Variant 9-90864655-A-C is Benign according to our data. Variant chr9-90864655-A-C is described in ClinVar as Benign. ClinVar VariationId is 776431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00609 (927/152296) while in subpopulation AFR AF = 0.0201 (834/41540). AF 95% confidence interval is 0.0189. There are 12 homozygotes in GnomAd4. There are 450 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 927 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003177.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYK	NM_003177.7	MANE Select	c.784A>C	p.Ile262Leu	missense	Exon 5 of 14	NP_003168.2
SYK	NM_001174167.3		c.784A>C	p.Ile262Leu	missense	Exon 5 of 14	NP_001167638.1	P43405-1
SYK	NM_001135052.4		c.784A>C	p.Ile262Leu	missense	Exon 5 of 13	NP_001128524.1	P43405-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYK	ENST00000375754.9	TSL:1 MANE Select	c.784A>C	p.Ile262Leu	missense	Exon 5 of 14	ENSP00000364907.4	P43405-1
SYK	ENST00000375746.1	TSL:1	c.784A>C	p.Ile262Leu	missense	Exon 5 of 14	ENSP00000364898.1	P43405-1
SYK	ENST00000375747.5	TSL:1	c.784A>C	p.Ile262Leu	missense	Exon 5 of 13	ENSP00000364899.1	P43405-2

Frequencies

GnomAD3 genomes

AF:

0.00607

AC:

924

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0200

Gnomad AMI

AF:

0.00549

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00764

GnomAD2 exomes

AF:

0.00183

AC:

461

AN:

251430

AF XY:

0.00141

show subpopulations

Gnomad AFR exome

AF:

0.0201

Gnomad AMR exome

AF:

0.00249

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000281

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000811

AC:

1185

AN:

1461828

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

547

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.0219

AC:

732

AN:

33476

American (AMR)

AF:

0.00311

AC:

139

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000139

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00381

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000136

AC:

151

AN:

1111962

Other (OTH)

AF:

0.00204

AC:

123

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

108

162

216

270

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00609

AC:

927

AN:

152296

Hom.:

Cov.:

AF XY:

0.00604

AC XY:

450

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0201

AC:

834

AN:

41540

American (AMR)

AF:

0.00353

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68016

Other (OTH)

AF:

0.00756

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

137

182

228

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00228

Hom.:

Bravo

AF:

0.00688

ESP6500AA

AF:

0.0161

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00189

AC:

229

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000652

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.11

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.60

MetaRNN

Benign

0.0061

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

PhyloP100

1.1

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.18

REVEL

Benign

0.046

Sift

Benign

0.72

Sift4G

Benign

0.72

Polyphen

0.0010

Vest4

0.16

MVP

0.72

MPC

0.62

ClinPred

0.0082

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.24

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over