rs280518

Variant names:

• chr19-10361959-C-G
• rs280518
• NM_003331.5:c.1774-4G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-10361959-C-G
• chr19-10361959-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003331.5(TYK2):​c.1774-4G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00759 in 1,613,930 control chromosomes in the GnomAD database, including 775 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (389 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (386 hom.)
• Consequence: TYK2 NM_003331.5 splice_region, intron
• Scores: Splicing: ADA: 0.0001158
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.761
• Publications: 5 publications found

Genes affected

TYK2 (HGNC:12440): (tyrosine kinase 2) This gene encodes a member of the tyrosine kinase and, more specifically, the Janus kinases (JAKs) protein families. This protein associates with the cytoplasmic domain of type I and type II cytokine receptors and promulgate cytokine signals by phosphorylating receptor subunits. It is also a component of both the type I and type III interferon signaling pathways. As such, it may play a role in anti-viral immunity. A mutation in this gene has been associated with Immunodeficiency 35. [provided by RefSeq, Sep 2020]

TYK2 Gene-Disease associations (from GenCC):

• immunodeficiency 35

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-10361959-C-G is Benign according to our data. Variant chr19-10361959-C-G is described in ClinVar as Benign. ClinVar VariationId is 137866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003331.5. 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
	TYK2	NM_003331.5	MANE Select	c.1774-4G>C		splice_region intron	N/A	NP_003322.3
	TYK2	NM_001385204.1		c.1774-4G>C		splice_region intron	N/A	NP_001372133.1
	TYK2	NM_001385203.1		c.1774-4G>C		splice_region intron	N/A	NP_001372132.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYK2	ENST00000525621.6	TSL:1 MANE Select	c.1774-4G>C		splice_region intron	N/A	ENSP00000431885.1	P29597
	TYK2	ENST00000524462.5	TSL:1	c.1219-4G>C		splice_region intron	N/A	ENSP00000433203.1	E9PM19
	TYK2	ENST00000531836.7	TSL:4	c.1774-4G>C		splice_region intron	N/A	ENSP00000436175.2	P29597

Frequencies

GnomAD3 genomes AF: 0.0404 AC: 6136 AN: 152038 Hom.: 389 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.0282

GnomAD2 exomes AF: 0.0109 AC: 2740 AN: 250838 AF XY: 0.00812

Gnomad AFR exome AF: 0.148

Gnomad AMR exome AF: 0.00773

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000309

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00418 AC: 6110 AN: 1461774 Hom.: 386 Cov.: 36 AF XY: 0.00354 AC XY: 2577 AN XY: 727204

African (AFR) AF: 0.148 AC: 4963 AN: 33480

American (AMR) AF: 0.00823 AC: 368 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 32 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86258

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53340

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.000192 AC: 214 AN: 1111982

Other (OTH) AF: 0.00813 AC: 491 AN: 60390

GnomAD4 genome AF: 0.0404 AC: 6146 AN: 152156 Hom.: 389 Cov.: 32 AF XY: 0.0394 AC XY: 2928 AN XY: 74388

African (AFR) AF: 0.140 AC: 5821 AN: 41470

American (AMR) AF: 0.0148 AC: 226 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68000

Other (OTH) AF: 0.0279 AC: 59 AN: 2112

Alfa AF: 0.00235 Hom.: 4

Bravo AF: 0.0467

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000711

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Immunodeficiency 35 (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.7
DANN	Benign	0.38
PhyloP100		-0.76
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.046
SpliceAI score (max)		0.16		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: rs280518; hg19: chr19-10472635;