rs12720270

Variant names:

• chr19-10365084-G-A
• rs12720270
• NM_003331.5:c.1012-36C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-10365084-G-A
• chr19-10365084-G-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.1012-36C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 1,565,406 control chromosomes in the GnomAD database, including 31,415 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2637 hom., cov: 33)
  • Exomes 𝑓: 0.19 (28778 hom.)
• Consequence: TYK2 NM_003331.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0140
• Publications: 44 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=-0.87).
• BP6: Variant 19-10365084-G-A is Benign according to our data. Variant chr19-10365084-G-A is described in ClinVar as Benign. ClinVar VariationId is 1257593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYK2	NM_003331.5	c.1012-36C>T		intron_variant	Intron 7 of 24	ENST00000525621.6	NP_003322.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYK2	ENST00000525621.6	c.1012-36C>T		intron_variant	Intron 7 of 24	1	NM_003331.5	ENSP00000431885.1

Frequencies

GnomAD3 genomes AF: 0.165 AC: 25031 AN: 152132 Hom.: 2636 Cov.: 33

Gnomad AFR AF: 0.0654

Gnomad AMI AF: 0.366

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.489

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.174

GnomAD2 exomes AF: 0.209 AC: 42480 AN: 203320 AF XY: 0.211

Gnomad AFR exome AF: 0.0629

Gnomad AMR exome AF: 0.163

Gnomad ASJ exome AF: 0.210

Gnomad EAS exome AF: 0.505

Gnomad FIN exome AF: 0.161

Gnomad NFE exome AF: 0.197

Gnomad OTH exome AF: 0.201

GnomAD4 exome AF: 0.194 AC: 274774 AN: 1413156 Hom.: 28778 Cov.: 32 AF XY: 0.195 AC XY: 136131 AN XY: 698046

African (AFR) AF: 0.0578 AC: 1894 AN: 32768

American (AMR) AF: 0.161 AC: 6575 AN: 40836

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 4807 AN: 23488

East Asian (EAS) AF: 0.422 AC: 16419 AN: 38898

South Asian (SAS) AF: 0.216 AC: 17136 AN: 79492

European-Finnish (FIN) AF: 0.165 AC: 7934 AN: 48112

Middle Eastern (MID) AF: 0.207 AC: 1152 AN: 5578

European-Non Finnish (NFE) AF: 0.191 AC: 206942 AN: 1085566

Other (OTH) AF: 0.204 AC: 11915 AN: 58418

GnomAD4 genome AF: 0.164 AC: 25043 AN: 152250 Hom.: 2637 Cov.: 33 AF XY: 0.165 AC XY: 12244 AN XY: 74426

African (AFR) AF: 0.0654 AC: 2717 AN: 41570

American (AMR) AF: 0.167 AC: 2552 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 779 AN: 3470

East Asian (EAS) AF: 0.490 AC: 2526 AN: 5158

South Asian (SAS) AF: 0.229 AC: 1105 AN: 4832

European-Finnish (FIN) AF: 0.151 AC: 1606 AN: 10612

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.191 AC: 13003 AN: 68004

Other (OTH) AF: 0.173 AC: 366 AN: 2112

Alfa AF: 0.161 Hom.: 493

Bravo AF: 0.164

Asia WGS AF: 0.316 AC: 1094 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

- -

Jul 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19567624, 31961910) -

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 31% of patients studied by a panel of primary immunodeficiencies. Number of patients: 30. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.2
DANN	Benign	0.44
PhyloP100		-0.014
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12720270; hg19: chr19-10475760; COSMIC: COSV53385751; COSMIC: COSV53385751;