chr15-74788737-G-A

Position:

• chr15-74788737-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004383.3(CSK):​c.-66+6017G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.435 in 154,224 control chromosomes in the GnomAD database, including 19,040 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 0.43 (18771 hom., cov: 33)
  • Exomes 𝑓: 0.49 (269 hom.)
• Consequence: CSK NM_004383.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0180

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]

CSK (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSK	NM_004383.3	c.-66+6017G>A		intron_variant		ENST00000220003.14	NP_004374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSK	ENST00000220003.14	c.-66+6017G>A		intron_variant		1	NM_004383.3	ENSP00000220003.9

Frequencies

GnomAD3 genomes AF: 0.435 AC: 66101 AN: 152060 Hom.: 18778 Cov.: 33

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.459

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.562

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.551

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.657

Gnomad OTH AF: 0.455

GnomAD3 exomes AF: 0.708 AC: 269 AN: 380 Hom.: 92 AF XY: 0.703 AC XY: 149 AN XY: 212

Gnomad ASJ exome AF: 0.500

Gnomad FIN exome AF: 0.750

Gnomad NFE exome AF: 0.712

Gnomad OTH exome AF: 0.600

GnomAD4 exome AF: 0.487 AC: 996 AN: 2046 Hom.: 269 Cov.: 0 AF XY: 0.502 AC XY: 511 AN XY: 1018

Gnomad4 AFR exome AF: 0.206

Gnomad4 AMR exome AF: 0.125

Gnomad4 ASJ exome AF: 0.250

Gnomad4 SAS exome AF: 0.233

Gnomad4 FIN exome AF: 0.875

Gnomad4 NFE exome AF: 0.661

Gnomad4 OTH exome AF: 0.313

GnomAD4 genome AF: 0.434 AC: 66077 AN: 152178 Hom.: 18771 Cov.: 33 AF XY: 0.421 AC XY: 31296 AN XY: 74390

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.358

Gnomad4 ASJ AF: 0.562

Gnomad4 EAS AF: 0.175

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.551

Gnomad4 NFE AF: 0.657

Gnomad4 OTH AF: 0.450

Alfa AF: 0.521 Hom.: 3515

Bravo AF: 0.414

Asia WGS AF: 0.165 AC: 580 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.1
DANN	Benign	0.87

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: rs2168518; hg19: chr15-75081078;