rs2168518

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]

MIR4513 (HGNC:41855): (microRNA 4513) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

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	UniProt
CSK	NM_004383.3	c.-66+6017G>A		intron_variant		ENST00000220003.14
MIR4513	NR_039738.1	n.21C>T		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSK	ENST00000220003.14	c.-66+6017G>A		intron_variant		1	NM_004383.3	P1
MIR4513	ENST00000581077.1	n.21C>T		mature_miRNA_variant	1/1

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;