rs34866753

Variant names:

• chr15-74801568-G-A
• rs34866753
• NM_004383.3:c.860G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.78
• Publications: 5 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 -20 ACMG points.

• 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 VariationId is 713186.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 = 0.00532 (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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 811 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSK	NM_004383.3	MANE Select	c.860G>A	p.Gly287Asp	missense	Exon 10 of 13	NP_004374.1	B2R6Q4
	CSK	NM_001127190.2		c.860G>A	p.Gly287Asp	missense	Exon 11 of 14	NP_001120662.1	P41240
	CSK	NM_001354988.2		c.860G>A	p.Gly287Asp	missense	Exon 12 of 15	NP_001341917.1	P41240

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSK	ENST00000220003.14	TSL:1 MANE Select	c.860G>A	p.Gly287Asp	missense	Exon 10 of 13	ENSP00000220003.9	P41240
	CSK	ENST00000439220.6	TSL:2	c.860G>A	p.Gly287Asp	missense	Exon 11 of 14	ENSP00000414764.2	P41240
	CSK	ENST00000567571.5	TSL:2	c.860G>A	p.Gly287Asp	missense	Exon 12 of 15	ENSP00000454906.1	P41240

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

GnomAD2 exomes AF: 0.00143 AC: 358 AN: 250994 AF XY: 0.00115

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 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

African (AFR) AF: 0.0183 AC: 613 AN: 33476

American (AMR) AF: 0.00123 AC: 55 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.000118 AC: 131 AN: 1111930

Other (OTH) AF: 0.00142 AC: 86 AN: 60384

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

African (AFR) AF: 0.0183 AC: 761 AN: 41566

American (AMR) AF: 0.00229 AC: 35 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68032

Other (OTH) AF: 0.00380 AC: 8 AN: 2108

Alfa AF: 0.00280 Hom.: 6

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.071
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.52	N
PhyloP100		3.8
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	0.80	N
REVEL	Benign	0.067
Sift	Benign	0.83	T
Sift4G	Benign	0.63	T
Polyphen		0.0060	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
Mutation Taster		=99/1	polymorphism

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