rs761141309

Variant names:

• chr19-10365836-C-A
• rs761141309
• NM_003331.5:c.692G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-10365836-C-A
• chr19-10365836-C-G
• chr19-10365836-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_001385204.1(TYK2):​c.692G>T​(p.Arg231Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,026 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R231W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TYK2 NM_001385204.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.253
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-10365837-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 840450.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001385204.1. 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.692G>T	p.Arg231Leu	missense	Exon 7 of 25	NP_003322.3
	TYK2	NM_001385204.1		c.692G>T	p.Arg231Leu	missense	Exon 7 of 25	NP_001372133.1
	TYK2	NM_001385203.1		c.692G>T	p.Arg231Leu	missense	Exon 7 of 26	NP_001372132.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYK2	ENST00000525621.6	TSL:1 MANE Select	c.692G>T	p.Arg231Leu	missense	Exon 7 of 25	ENSP00000431885.1
	TYK2	ENST00000524462.5	TSL:1	c.137G>T	p.Arg46Leu	missense	Exon 3 of 21	ENSP00000433203.1
	TYK2	ENST00000531836.7	TSL:4	c.692G>T	p.Arg231Leu	missense	Exon 7 of 25	ENSP00000436175.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460026 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726360

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111762

Other (OTH) AF: 0.00 AC: 0 AN: 60306

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.19	N
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		0.25
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Benign	0.17
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.79	P
Vest4		0.55
MutPred		0.68		Loss of methylation at R231 (P = 0.0197)
MVP		0.80
MPC		0.90
ClinPred		0.77	D
GERP RS		1.1
PromoterAI		-0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.63
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs761141309; hg19: chr19-10476512; COSMIC: COSV99314631; COSMIC: COSV99314631;