rs2229730

Positions:

• chr15-74801048-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_004383.3(CSK):​c.759C>T​(p.Gly253=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0642 in 1,613,282 control chromosomes in the GnomAD database, including 8,203 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.064 (631 hom., cov: 33)
  • Exomes 𝑓: 0.064 (7572 hom.)
• Consequence: CSK NM_004383.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.66

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP7: Synonymous conserved (PhyloP=-2.66 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSK	NM_004383.3	c.759C>T	p.Gly253=	synonymous_variant	9/13	ENST00000220003.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSK	ENST00000220003.14	c.759C>T	p.Gly253=	synonymous_variant	9/13	1	NM_004383.3	P1

Frequencies

GnomAD3 genomes AF: 0.0638 AC: 9697 AN: 152070 Hom.: 628 Cov.: 33

Gnomad AFR AF: 0.0455

Gnomad AMI AF: 0.0868

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.0600

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.0670

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0364

Gnomad OTH AF: 0.0684

GnomAD3 exomes AF: 0.105 AC: 26406 AN: 251010 Hom.: 2864 AF XY: 0.113 AC XY: 15373 AN XY: 135828

Gnomad AFR exome AF: 0.0460

Gnomad AMR exome AF: 0.168

Gnomad ASJ exome AF: 0.0619

Gnomad EAS exome AF: 0.168

Gnomad SAS exome AF: 0.334

Gnomad FIN exome AF: 0.0614

Gnomad NFE exome AF: 0.0358

Gnomad OTH exome AF: 0.0869

GnomAD4 exome AF: 0.0643 AC: 93917 AN: 1461094 Hom.: 7572 Cov.: 33 AF XY: 0.0718 AC XY: 52210 AN XY: 726866

Gnomad4 AFR exome AF: 0.0422

Gnomad4 AMR exome AF: 0.158

Gnomad4 ASJ exome AF: 0.0633

Gnomad4 EAS exome AF: 0.175

Gnomad4 SAS exome AF: 0.328

Gnomad4 FIN exome AF: 0.0564

Gnomad4 NFE exome AF: 0.0362

Gnomad4 OTH exome AF: 0.0798

GnomAD4 genome AF: 0.0638 AC: 9716 AN: 152188 Hom.: 631 Cov.: 33 AF XY: 0.0714 AC XY: 5314 AN XY: 74422

Gnomad4 AFR AF: 0.0455

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.0600

Gnomad4 EAS AF: 0.173

Gnomad4 SAS AF: 0.355

Gnomad4 FIN AF: 0.0670

Gnomad4 NFE AF: 0.0364

Gnomad4 OTH AF: 0.0753

Alfa AF: 0.0434 Hom.: 114

Bravo AF: 0.0607

Asia WGS AF: 0.316 AC: 1095 AN: 3478

EpiCase AF: 0.0360

EpiControl AF: 0.0408

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.0
DANN	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2229730; hg19: chr15-75093389;