rs12720222

Variant names:

• chr19-10378495-C-T
• rs12720222
• NM_003331.5:c.-20-69G>A

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.-20-69G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.08 in 1,304,520 control chromosomes in the GnomAD database, including 4,598 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.098 (900 hom., cov: 32)
  • Exomes 𝑓: 0.078 (3698 hom.)
• Consequence: TYK2 NM_003331.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.643
• Publications: 9 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: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-10378495-C-T is Benign according to our data. Variant chr19-10378495-C-T is described in ClinVar as Benign. ClinVar VariationId is 676029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003331.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYK2	NM_003331.5	MANE Select	c.-20-69G>A		intron	N/A	NP_003322.3
	TYK2	NM_001385204.1		c.-20-69G>A		intron	N/A	NP_001372133.1
	TYK2	NM_001385203.1		c.-20-69G>A		intron	N/A	NP_001372132.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYK2	ENST00000525621.6	TSL:1 MANE Select	c.-20-69G>A		intron	N/A	ENSP00000431885.1	P29597
	TYK2	ENST00000524462.5	TSL:1	c.-91+2015G>A		intron	N/A	ENSP00000433203.1	E9PM19
	TYK2	ENST00000531836.7	TSL:4	c.-20-69G>A		intron	N/A	ENSP00000436175.2	P29597

Frequencies

GnomAD3 genomes AF: 0.0978 AC: 14875 AN: 152136 Hom.: 893 Cov.: 32

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.0568

Gnomad ASJ AF: 0.0615

Gnomad EAS AF: 0.0330

Gnomad SAS AF: 0.0645

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0737

Gnomad OTH AF: 0.0856

GnomAD4 exome AF: 0.0776 AC: 89469 AN: 1152266 Hom.: 3698 Cov.: 15 AF XY: 0.0768 AC XY: 44544 AN XY: 580134

African (AFR) AF: 0.171 AC: 4654 AN: 27254

American (AMR) AF: 0.0448 AC: 1642 AN: 36690

Ashkenazi Jewish (ASJ) AF: 0.0610 AC: 1435 AN: 23532

East Asian (EAS) AF: 0.0467 AC: 1665 AN: 35620

South Asian (SAS) AF: 0.0702 AC: 5299 AN: 75462

European-Finnish (FIN) AF: 0.113 AC: 3982 AN: 35208

Middle Eastern (MID) AF: 0.0645 AC: 233 AN: 3610

European-Non Finnish (NFE) AF: 0.0770 AC: 66593 AN: 864456

Other (OTH) AF: 0.0786 AC: 3966 AN: 50434

GnomAD4 genome AF: 0.0979 AC: 14906 AN: 152254 Hom.: 900 Cov.: 32 AF XY: 0.0978 AC XY: 7278 AN XY: 74440

African (AFR) AF: 0.164 AC: 6821 AN: 41542

American (AMR) AF: 0.0567 AC: 867 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0615 AC: 213 AN: 3466

East Asian (EAS) AF: 0.0327 AC: 169 AN: 5172

South Asian (SAS) AF: 0.0637 AC: 308 AN: 4832

European-Finnish (FIN) AF: 0.118 AC: 1253 AN: 10618

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0737 AC: 5012 AN: 68012

Other (OTH) AF: 0.0852 AC: 180 AN: 2112

Alfa AF: 0.0883 Hom.: 97

Bravo AF: 0.0980

Asia WGS AF: 0.0730 AC: 253 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.1
DANN	Benign	0.51
PhyloP100		-0.64
PromoterAI		-0.0016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs12720222; hg19: chr19-10489171;