rs775578531

Variant names:

• chr19-10353648-T-C
• rs775578531
• NM_003331.5:c.2909-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003331.5(TYK2):​c.2909-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000532 in 1,316,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000053 (0 hom.)
• Consequence: TYK2 NM_003331.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.63
• Publications: 0 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: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-10353648-T-C is Pathogenic according to our data. Variant chr19-10353648-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 583161.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYK2	NM_003331.5	c.2909-2A>G		splice_acceptor_variant, intron_variant	Intron 20 of 24	ENST00000525621.6	NP_003322.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYK2	ENST00000525621.6	c.2909-2A>G		splice_acceptor_variant, intron_variant	Intron 20 of 24	1	NM_003331.5	ENSP00000431885.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000719 AC: 1 AN: 139108 AF XY: 0.0000134

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000148

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000532 AC: 7 AN: 1316922 Hom.: 0 Cov.: 31 AF XY: 0.00000468 AC XY: 3 AN XY: 640674

African (AFR) AF: 0.00 AC: 0 AN: 29378

American (AMR) AF: 0.00 AC: 0 AN: 25152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18772

East Asian (EAS) AF: 0.00 AC: 0 AN: 36718

South Asian (SAS) AF: 0.00 AC: 0 AN: 61100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3868

European-Non Finnish (NFE) AF: 0.00000672 AC: 7 AN: 1041754

Other (OTH) AF: 0.00 AC: 0 AN: 53956

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000865 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency 35 Pathogenic:1

Apr 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 20 of the TYK2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TYK2 are known to be pathogenic (PMID: 22402565, 26304966). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 583161). This variant has not been reported in the literature in individuals affected with TYK2-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		4.6
GERP RS		5.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.42		Position offset: -10
DS_AL_spliceai		0.98		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs775578531; hg19: chr19-10464324;