rs2229730

Variant names:

• chr15-74801048-C-T
• rs2229730
• NM_004383.3:c.759C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_004383.3(CSK):​c.759C>T​(p.Gly253Gly) 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
• Publications: 15 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004383.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSK	NM_004383.3	MANE Select	c.759C>T	p.Gly253Gly	synonymous	Exon 9 of 13	NP_004374.1
	CSK	NM_001127190.2		c.759C>T	p.Gly253Gly	synonymous	Exon 10 of 14	NP_001120662.1
	CSK	NM_001354988.2		c.759C>T	p.Gly253Gly	synonymous	Exon 11 of 15	NP_001341917.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSK	ENST00000220003.14	TSL:1 MANE Select	c.759C>T	p.Gly253Gly	synonymous	Exon 9 of 13	ENSP00000220003.9
	CSK	ENST00000439220.6	TSL:2	c.759C>T	p.Gly253Gly	synonymous	Exon 10 of 14	ENSP00000414764.2
	CSK	ENST00000567571.5	TSL:2	c.759C>T	p.Gly253Gly	synonymous	Exon 11 of 15	ENSP00000454906.1

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

GnomAD2 exomes AF: 0.105 AC: 26406 AN: 251010 AF XY: 0.113

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 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

African (AFR) AF: 0.0422 AC: 1414 AN: 33478

American (AMR) AF: 0.158 AC: 7074 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0633 AC: 1654 AN: 26136

East Asian (EAS) AF: 0.175 AC: 6946 AN: 39700

South Asian (SAS) AF: 0.328 AC: 28248 AN: 86252

European-Finnish (FIN) AF: 0.0564 AC: 2968 AN: 52664

Middle Eastern (MID) AF: 0.0876 AC: 505 AN: 5768

European-Non Finnish (NFE) AF: 0.0362 AC: 40289 AN: 1111986

Other (OTH) AF: 0.0798 AC: 4819 AN: 60388

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

African (AFR) AF: 0.0455 AC: 1887 AN: 41506

American (AMR) AF: 0.103 AC: 1570 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0600 AC: 208 AN: 3466

East Asian (EAS) AF: 0.173 AC: 897 AN: 5172

South Asian (SAS) AF: 0.355 AC: 1708 AN: 4816

European-Finnish (FIN) AF: 0.0670 AC: 711 AN: 10614

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0364 AC: 2476 AN: 68000

Other (OTH) AF: 0.0753 AC: 159 AN: 2112

Alfa AF: 0.0433 Hom.: 153

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.0
DANN	Benign	0.76
PhyloP100		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2229730; hg19: chr15-75093389;