rs12720299

Variant names:

• chr19-10357992-C-G
• rs12720299
• NM_003331.5:c.2311+11G>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.2311+11G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,613,420 control chromosomes in the GnomAD database, including 16,071 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1156 hom., cov: 33)
  • Exomes 𝑓: 0.14 (14915 hom.)
• Consequence: TYK2 NM_003331.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.35
• Publications: 12 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 19-10357992-C-G is Benign according to our data. Variant chr19-10357992-C-G is described in ClinVar as Benign. ClinVar VariationId is 137868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.143 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYK2	NM_003331.5	MANE Select	c.2311+11G>C		intron	N/A	NP_003322.3
	TYK2	NM_001385204.1		c.2311+11G>C		intron	N/A	NP_001372133.1
	TYK2	NM_001385203.1		c.2311+11G>C		intron	N/A	NP_001372132.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYK2	ENST00000525621.6	TSL:1 MANE Select	c.2311+11G>C		intron	N/A	ENSP00000431885.1
	TYK2	ENST00000524462.5	TSL:1	c.1756+11G>C		intron	N/A	ENSP00000433203.1
	TYK2	ENST00000531836.7	TSL:4	c.2311+11G>C		intron	N/A	ENSP00000436175.2

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17890 AN: 152170 Hom.: 1151 Cov.: 33

Gnomad AFR AF: 0.0842

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.0871

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.0333

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.116

GnomAD2 exomes AF: 0.119 AC: 29716 AN: 249742 AF XY: 0.123

Gnomad AFR exome AF: 0.0823

Gnomad AMR exome AF: 0.0631

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.0302

Gnomad FIN exome AF: 0.142

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.139 AC: 203118 AN: 1461132 Hom.: 14915 Cov.: 33 AF XY: 0.140 AC XY: 101483 AN XY: 726872

African (AFR) AF: 0.0827 AC: 2770 AN: 33480

American (AMR) AF: 0.0669 AC: 2992 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 2908 AN: 26136

East Asian (EAS) AF: 0.0244 AC: 968 AN: 39688

South Asian (SAS) AF: 0.150 AC: 12949 AN: 86258

European-Finnish (FIN) AF: 0.142 AC: 7462 AN: 52708

Middle Eastern (MID) AF: 0.114 AC: 657 AN: 5760

European-Non Finnish (NFE) AF: 0.148 AC: 164360 AN: 1111990

Other (OTH) AF: 0.133 AC: 8052 AN: 60390

GnomAD4 genome AF: 0.118 AC: 17912 AN: 152288 Hom.: 1156 Cov.: 33 AF XY: 0.116 AC XY: 8635 AN XY: 74456

African (AFR) AF: 0.0844 AC: 3509 AN: 41568

American (AMR) AF: 0.0871 AC: 1331 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 402 AN: 3470

East Asian (EAS) AF: 0.0326 AC: 169 AN: 5178

South Asian (SAS) AF: 0.140 AC: 677 AN: 4828

European-Finnish (FIN) AF: 0.139 AC: 1480 AN: 10616

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.146 AC: 9913 AN: 68026

Other (OTH) AF: 0.121 AC: 255 AN: 2110

Alfa AF: 0.129 Hom.: 266

Bravo AF: 0.113

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Immunodeficiency 35 (3)
-	-	3	not specified (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.031
DANN	Benign	0.35
PhyloP100		-2.4
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: rs12720299; hg19: chr19-10468668;