15-74801568-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_004383.3(CSK):c.860G>A(p.Gly287Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00106 in 1,614,016 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 0.0053 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00061 (15 hom.)
• Consequence: CSK NM_004383.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.78

Genes affected

CSK (HGNC:2444): (C-terminal Src kinase) The protein encoded by this gene is involved in multiple pathways, including the regulation of Src family kinases. It plays an important role in T-cell activation through its association with the protein encoded by the protein tyrosine phosphatase, non-receptor type 22 (PTPN22) gene. This protein also phosphorylates C-terminal tyrosine residues on multiple substrates, including the protein encoded by the SRC proto-oncogene, non-receptor tyrosine kinase gene. Phosphorylation suppresses the kinase activity of the Src family tyrosine kinases. An intronic polymorphism (rs34933034) in this gene has been found to affect B-cell activation and is associated with systemic lupus erythematosus (SLE). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CSK
• BP4: Computational evidence support a benign effect (MetaRNN=0.009608954).
• BP6: Variant 15-74801568-G-A is Benign according to our data. Variant chr15-74801568-G-A is described in ClinVar as [Benign]. Clinvar id is 713186.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00532 (811/152322) while in subpopulation AFR AF= 0.0183 (761/41566). AF 95% confidence interval is 0.0172. There are 8 homozygotes in gnomad4. There are 368 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 810 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSK	NM_004383.3	c.860G>A	p.Gly287Asp	missense_variant	10/13	ENST00000220003.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSK	ENST00000220003.14	c.860G>A	p.Gly287Asp	missense_variant	10/13	1	NM_004383.3	P1

Frequencies

GnomAD3 genomes AF: 0.00532 AC: 810 AN: 152204 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

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: 0.0000882

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.00143 AC: 358 AN: 250994 Hom.: 3 AF XY: 0.00115 AC XY: 156 AN XY: 135670

Gnomad AFR exome AF: 0.0177

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000614 AC: 897 AN: 1461694 Hom.: 15 Cov.: 32 AF XY: 0.000524 AC XY: 381 AN XY: 727136

Gnomad4 AFR exome AF: 0.0183

Gnomad4 AMR exome AF: 0.00123

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: 0.000118

Gnomad4 OTH exome AF: 0.00142

GnomAD4 genome AF: 0.00532 AC: 811 AN: 152322 Hom.: 8 Cov.: 33 AF XY: 0.00494 AC XY: 368 AN XY: 74494

Gnomad4 AFR AF: 0.0183

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00201 Hom.: 1

Bravo AF: 0.00602

ESP6500AA AF: 0.0164 AC: 72

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00185 AC: 225

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000415

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

Jun 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	21
Dann	Benign	0.89
DEOGEN2	Uncertain	0.48	T;T;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.071
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.0096	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.52	N;N;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	0.80	N;N;N
REVEL	Benign	0.067
Sift	Benign	0.83	T;T;T
Sift4G	Benign	0.63	T;T;T
Polyphen		0.0060	B;B;B
Vest4		0.62
MVP		0.31
MPC		1.6
ClinPred		0.012	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.45
gMVP		0.85

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: rs34866753; hg19: chr15-75093909; COSMIC: COSV54972835; COSMIC: COSV54972835;