dbSNP rs775578531: TYK2:c.2909-2A>G (chr19-10353648-T-C) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001385204.1(TYK2):c.3119-2A>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_001385204.1 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

Variant links:

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)

TYK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001385204.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TYK2	NM_003331.5	MANE Select	c.2909-2A>G	splice_acceptor intron	N/A	NP_003322.3
TYK2	NM_001385204.1		c.3119-2A>G	splice_acceptor intron	N/A	NP_001372133.1
TYK2	NM_001385203.1		c.2990-2A>G	splice_acceptor intron	N/A	NP_001372132.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TYK2	ENST00000525621.6	TSL:1 MANE Select	c.2909-2A>G	splice_acceptor intron	N/A	ENSP00000431885.1
TYK2	ENST00000524462.5	TSL:1	c.2354-2A>G	splice_acceptor intron	N/A	ENSP00000433203.1
TYK2	ENST00000531836.7	TSL:4	c.2909-2A>G	splice_acceptor intron	N/A	ENSP00000436175.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000719

AC:

AN:

139108

AF XY:

0.0000134

show subpopulations

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:

AN:

1316922

Hom.:

Cov.:

AF XY:

0.00000468

AC XY:

AN XY:

640674

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29378

American (AMR)

AF:

0.00

AC:

AN:

25152

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18772

East Asian (EAS)

AF:

0.00

AC:

AN:

36718

South Asian (SAS)

AF:

0.00

AC:

AN:

61100

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46224

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3868

European-Non Finnish (NFE)

AF:

0.00000672

AC:

AN:

1041754

Other (OTH)

AF:

0.00

AC:

AN:

53956

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000865

AC:

ClinVar

ClinVar submissions as Germline

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Immunodeficiency 35 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.95

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)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over