NM_003331.5:c.629+26T>C

Variant names:

• chr19-10366391-A-G
• rs34725611
• NM_003331.5:c.629+26T>C

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.629+26T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 1,604,892 control chromosomes in the GnomAD database, including 65,031 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4868 hom., cov: 31)
  • Exomes 𝑓: 0.28 (60163 hom.)
• Consequence: TYK2 NM_003331.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.15
• Publications: 40 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 19-10366391-A-G is Benign according to our data. Variant chr19-10366391-A-G is described in ClinVar as Benign. ClinVar VariationId is 1243741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.498 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYK2	NM_003331.5	c.629+26T>C		intron_variant	Intron 6 of 24	ENST00000525621.6	NP_003322.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYK2	ENST00000525621.6	c.629+26T>C		intron_variant	Intron 6 of 24	1	NM_003331.5	ENSP00000431885.1

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35563 AN: 151644 Hom.: 4863 Cov.: 31

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.514

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.280

Gnomad NFE AF: 0.279

Gnomad OTH AF: 0.247

GnomAD2 exomes AF: 0.277 AC: 68949 AN: 248766 AF XY: 0.280

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.199

Gnomad ASJ exome AF: 0.308

Gnomad EAS exome AF: 0.536

Gnomad FIN exome AF: 0.243

Gnomad NFE exome AF: 0.286

Gnomad OTH exome AF: 0.281

GnomAD4 exome AF: 0.282 AC: 410458 AN: 1453174 Hom.: 60163 Cov.: 32 AF XY: 0.282 AC XY: 203785 AN XY: 721412

African (AFR) AF: 0.103 AC: 3417 AN: 33324

American (AMR) AF: 0.204 AC: 9089 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 7971 AN: 25860

East Asian (EAS) AF: 0.445 AC: 17557 AN: 39464

South Asian (SAS) AF: 0.276 AC: 23729 AN: 85926

European-Finnish (FIN) AF: 0.250 AC: 13313 AN: 53234

Middle Eastern (MID) AF: 0.290 AC: 1640 AN: 5660

European-Non Finnish (NFE) AF: 0.286 AC: 316207 AN: 1105094

Other (OTH) AF: 0.292 AC: 17535 AN: 60062

GnomAD4 genome AF: 0.234 AC: 35577 AN: 151718 Hom.: 4868 Cov.: 31 AF XY: 0.234 AC XY: 17315 AN XY: 74102

African (AFR) AF: 0.111 AC: 4571 AN: 41350

American (AMR) AF: 0.227 AC: 3453 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1126 AN: 3468

East Asian (EAS) AF: 0.514 AC: 2648 AN: 5148

South Asian (SAS) AF: 0.287 AC: 1380 AN: 4802

European-Finnish (FIN) AF: 0.238 AC: 2497 AN: 10482

Middle Eastern (MID) AF: 0.288 AC: 84 AN: 292

European-Non Finnish (NFE) AF: 0.279 AC: 18925 AN: 67930

Other (OTH) AF: 0.246 AC: 516 AN: 2100

Alfa AF: 0.253 Hom.: 1026

Bravo AF: 0.232

Asia WGS AF: 0.355 AC: 1230 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 36% of patients studied by a panel of primary immunodeficiencies. Number of patients: 35. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.65
DANN	Benign	0.62
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34725611; hg19: chr19-10477067; COSMIC: COSV53385765; COSMIC: COSV53385765;