19-10378293-G-T

Variant names:

• chr19-10378293-G-T
• rs56295652
• NM_003331.5:c.114C>A

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.114C>A​(p.Gly38Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,612,854 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G38G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0023 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (50 hom.)
• Consequence: TYK2 NM_003331.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.45
• Publications: 7 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-10378293-G-T is Benign according to our data. Variant chr19-10378293-G-T is described in ClinVar as Benign. ClinVar VariationId is 327961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.45 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00233 (355/152228) while in subpopulation EAS AF = 0.0522 (270/5174). AF 95% confidence interval is 0.0471. There are 9 homozygotes in GnomAd4. There are 192 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.114C>A	p.Gly38Gly	synonymous	Exon 3 of 25	NP_003322.3
	TYK2	NM_001385204.1		c.114C>A	p.Gly38Gly	synonymous	Exon 3 of 25	NP_001372133.1
	TYK2	NM_001385203.1		c.114C>A	p.Gly38Gly	synonymous	Exon 3 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.114C>A	p.Gly38Gly	synonymous	Exon 3 of 25	ENSP00000431885.1
	TYK2	ENST00000524462.5	TSL:1	c.-91+2217C>A		intron	N/A	ENSP00000433203.1
	TYK2	ENST00000531836.7	TSL:4	c.114C>A	p.Gly38Gly	synonymous	Exon 3 of 25	ENSP00000436175.2

Frequencies

GnomAD3 genomes AF: 0.00234 AC: 356 AN: 152110 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0523

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00428 AC: 1071 AN: 249962 AF XY: 0.00393

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0536

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.00117 AC: 1704 AN: 1460626 Hom.: 50 Cov.: 32 AF XY: 0.00110 AC XY: 801 AN XY: 726604

African (AFR) AF: 0.000717 AC: 24 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0309 AC: 1227 AN: 39700

South Asian (SAS) AF: 0.00134 AC: 116 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000360 AC: 40 AN: 1111972

Other (OTH) AF: 0.00484 AC: 292 AN: 60378

GnomAD4 genome AF: 0.00233 AC: 355 AN: 152228 Hom.: 9 Cov.: 32 AF XY: 0.00258 AC XY: 192 AN XY: 74434

African (AFR) AF: 0.00128 AC: 53 AN: 41524

American (AMR) AF: 0.000458 AC: 7 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.0522 AC: 270 AN: 5174

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68002

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000354 Hom.: 0

Bravo AF: 0.00246

Asia WGS AF: 0.0350 AC: 120 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.053
DANN	Benign	0.42
PhyloP100		-3.5
PromoterAI		0.064	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs56295652; hg19: chr19-10488969; COSMIC: COSV53385080;