chr19-10361776-G-A

Variant names:

• chr19-10361776-G-A
• rs12720355
• NM_003331.5:c.1953C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003331.5(TYK2):​c.1953C>T​(p.Ile651Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,612,786 control chromosomes in the GnomAD database, including 179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (17 hom., cov: 31)
  • Exomes 𝑓: 0.014 (162 hom.)
• Consequence: TYK2 NM_003331.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.44
• Publications: 11 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 19-10361776-G-A is Benign according to our data. Variant chr19-10361776-G-A is described in ClinVar as Benign. ClinVar VariationId is 259042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.44 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00999 (1514/151540) while in subpopulation NFE AF = 0.0159 (1077/67864). AF 95% confidence interval is 0.0151. There are 17 homozygotes in GnomAd4. There are 730 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

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.1953C>T	p.Ile651Ile	synonymous	Exon 13 of 25	NP_003322.3
	TYK2	NM_001385204.1		c.1953C>T	p.Ile651Ile	synonymous	Exon 13 of 25	NP_001372133.1
	TYK2	NM_001385203.1		c.1953C>T	p.Ile651Ile	synonymous	Exon 13 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.1953C>T	p.Ile651Ile	synonymous	Exon 13 of 25	ENSP00000431885.1	P29597
	TYK2	ENST00000524462.5	TSL:1	c.1398C>T	p.Ile466Ile	synonymous	Exon 9 of 21	ENSP00000433203.1	E9PM19
	TYK2	ENST00000531836.7	TSL:4	c.1953C>T	p.Ile651Ile	synonymous	Exon 13 of 25	ENSP00000436175.2	P29597

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1514 AN: 151418 Hom.: 17 Cov.: 31

Gnomad AFR AF: 0.00250

Gnomad AMI AF: 0.0287

Gnomad AMR AF: 0.00737

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00751

Gnomad FIN AF: 0.0125

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.00719

GnomAD2 exomes AF: 0.00957 AC: 2398 AN: 250616 AF XY: 0.00984

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.00492

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0123

Gnomad NFE exome AF: 0.0142

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.0140 AC: 20398 AN: 1461246 Hom.: 162 Cov.: 36 AF XY: 0.0139 AC XY: 10091 AN XY: 726978

African (AFR) AF: 0.00221 AC: 74 AN: 33476

American (AMR) AF: 0.00543 AC: 243 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00413 AC: 108 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00663 AC: 572 AN: 86258

European-Finnish (FIN) AF: 0.0118 AC: 623 AN: 52940

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5760

European-Non Finnish (NFE) AF: 0.0162 AC: 18066 AN: 1111902

Other (OTH) AF: 0.0116 AC: 699 AN: 60372

GnomAD4 genome AF: 0.00999 AC: 1514 AN: 151540 Hom.: 17 Cov.: 31 AF XY: 0.00986 AC XY: 730 AN XY: 74058

African (AFR) AF: 0.00250 AC: 103 AN: 41248

American (AMR) AF: 0.00736 AC: 112 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5110

South Asian (SAS) AF: 0.00751 AC: 36 AN: 4792

European-Finnish (FIN) AF: 0.0125 AC: 132 AN: 10524

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.0159 AC: 1077 AN: 67864

Other (OTH) AF: 0.00712 AC: 15 AN: 2108

Alfa AF: 0.0131 Hom.: 47

Bravo AF: 0.00936

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0145

EpiControl AF: 0.0132

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Immunodeficiency 35 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.8
DANN	Benign	0.63
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism

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: rs12720355; hg19: chr19-10472452; COSMIC: COSV53385701; COSMIC: COSV53385701;