chr19-10365586-G-A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP6_Very_StrongBP7BS1BS2

The NM_003331.5(TYK2):​c.942C>T​(p.His314His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,614,100 control chromosomes in the GnomAD database, including 38 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0080 ( 16 hom., cov: 32)
Exomes 𝑓: 0.0011 ( 22 hom. )

Consequence

TYK2
NM_003331.5 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.38

Publications

4 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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP6
Variant 19-10365586-G-A is Benign according to our data. Variant chr19-10365586-G-A is described in ClinVar as [Benign]. Clinvar id is 327952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-2.38 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00798 (1215/152282) while in subpopulation AFR AF = 0.0267 (1110/41572). AF 95% confidence interval is 0.0254. There are 16 homozygotes in GnomAd4. There are 585 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TYK2NM_003331.5 linkc.942C>T p.His314His synonymous_variant Exon 7 of 25 ENST00000525621.6 NP_003322.3 P29597A0A024R7E4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TYK2ENST00000525621.6 linkc.942C>T p.His314His synonymous_variant Exon 7 of 25 1 NM_003331.5 ENSP00000431885.1 P29597

Frequencies

GnomAD3 genomes
AF:
0.00788
AC:
1199
AN:
152164
Hom.:
16
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0264
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00393
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00518
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000132
Gnomad OTH
AF:
0.00383
GnomAD2 exomes
AF:
0.00263
AC:
659
AN:
250432
AF XY:
0.00236
show subpopulations
Gnomad AFR exome
AF:
0.0270
Gnomad AMR exome
AF:
0.00214
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000547
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000706
Gnomad OTH exome
AF:
0.00164
GnomAD4 exome
AF:
0.00114
AC:
1663
AN:
1461818
Hom.:
22
Cov.:
33
AF XY:
0.00117
AC XY:
851
AN XY:
727220
show subpopulations
African (AFR)
AF:
0.0273
AC:
914
AN:
33480
American (AMR)
AF:
0.00233
AC:
104
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26126
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39700
South Asian (SAS)
AF:
0.00430
AC:
371
AN:
86258
European-Finnish (FIN)
AF:
0.0000375
AC:
2
AN:
53364
Middle Eastern (MID)
AF:
0.00173
AC:
10
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000917
AC:
102
AN:
1112004
Other (OTH)
AF:
0.00263
AC:
159
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.489
Heterozygous variant carriers
0
102
204
305
407
509
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
40
80
120
160
200
<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
AF:
0.00798
AC:
1215
AN:
152282
Hom.:
16
Cov.:
32
AF XY:
0.00786
AC XY:
585
AN XY:
74440
show subpopulations
African (AFR)
AF:
0.0267
AC:
1110
AN:
41572
American (AMR)
AF:
0.00392
AC:
60
AN:
15302
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3464
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5156
South Asian (SAS)
AF:
0.00539
AC:
26
AN:
4824
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:
0.000132
AC:
9
AN:
68030
Other (OTH)
AF:
0.00426
AC:
9
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.497
Heterozygous variant carriers
0
63
127
190
254
317
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
20
40
60
80
100
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00474
Hom.:
0
Bravo
AF:
0.00931
Asia WGS
AF:
0.00404
AC:
14
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000178

ClinVar

Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Immunodeficiency 35 Benign:2
Jan 29, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1
Mar 18, 2016
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.78
CADD
Benign
0.59
DANN
Benign
0.52
PhyloP100
-2.4
PromoterAI
0.015
Neutral
Mutation Taster
=100/0
polymorphism

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

Other links and lift over

dbSNP: rs12720266; hg19: chr19-10476262; API