rs199686420

Variant names:

• chr19-18059963-A-G
• rs199686420
• NM_005535.3:c.1914T>C

Your query was ambiguous. Multiple possible variants found:

• chr19-18059963-A-G
• chr19-18059963-A-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_005535.3(IL12RB1):​c.1914T>C​(p.Pro638Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,598,992 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: IL12RB1 NM_005535.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.07
• Publications: 1 publications found

Genes affected

IL12RB1 (HGNC:5971): (interleukin 12 receptor subunit beta 1) The protein encoded by this gene is a type I transmembrane protein that belongs to the hemopoietin receptor superfamily. This protein binds to interleukine 12 (IL12) with a low affinity, and is thought to be a part of IL12 receptor complex. This protein forms a disulfide-linked oligomer, which is required for its IL12 binding activity. The coexpression of this and IL12RB2 proteins was shown to lead to the formation of high-affinity IL12 binding sites and reconstitution of IL12 dependent signaling. Mutations in this gene impair the development of interleukin-17-producing T lymphocytes and result in increased susceptibility to mycobacterial and Salmonella infections. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

IL12RB1 Gene-Disease associations (from GenCC):

• Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 19-18059963-A-G is Benign according to our data. Variant chr19-18059963-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 328575.
• BP7: Synonymous conserved (PhyloP=-1.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00125 (190/152114) while in subpopulation AMR AF = 0.00157 (24/15262). AF 95% confidence interval is 0.00116. There are 2 homozygotes in GnomAd4. There are 93 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005535.3. 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
	IL12RB1	NM_005535.3	MANE Select	c.1914T>C	p.Pro638Pro	synonymous	Exon 16 of 17	NP_005526.1	P42701-1
	IL12RB1	NM_001290024.2		c.2034T>C	p.Pro678Pro	synonymous	Exon 17 of 18	NP_001276953.1
	IL12RB1	NM_001440424.1		c.1935T>C	p.Pro645Pro	synonymous	Exon 16 of 17	NP_001427353.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL12RB1	ENST00000593993.7	TSL:1 MANE Select	c.1914T>C	p.Pro638Pro	synonymous	Exon 16 of 17	ENSP00000472165.2	P42701-1
	IL12RB1	ENST00000600835.6	TSL:1	c.1914T>C	p.Pro638Pro	synonymous	Exon 17 of 18	ENSP00000470788.1	P42701-1

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 190 AN: 151996 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00153 AC: 349 AN: 227470 AF XY: 0.00155

Gnomad AFR exome AF: 0.000301

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00977

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000147

Gnomad NFE exome AF: 0.00183

Gnomad OTH exome AF: 0.00230

GnomAD4 exome AF: 0.00145 AC: 2092 AN: 1446878 Hom.: 3 Cov.: 31 AF XY: 0.00144 AC XY: 1038 AN XY: 718768

African (AFR) AF: 0.000332 AC: 11 AN: 33090

American (AMR) AF: 0.00143 AC: 61 AN: 42700

Ashkenazi Jewish (ASJ) AF: 0.0105 AC: 270 AN: 25772

East Asian (EAS) AF: 0.00 AC: 0 AN: 39084

South Asian (SAS) AF: 0.00 AC: 0 AN: 83836

European-Finnish (FIN) AF: 0.0000761 AC: 4 AN: 52538

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5752

European-Non Finnish (NFE) AF: 0.00149 AC: 1648 AN: 1104246

Other (OTH) AF: 0.00147 AC: 88 AN: 59860

GnomAD4 genome AF: 0.00125 AC: 190 AN: 152114 Hom.: 2 Cov.: 32 AF XY: 0.00125 AC XY: 93 AN XY: 74370

African (AFR) AF: 0.000313 AC: 13 AN: 41478

American (AMR) AF: 0.00157 AC: 24 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00138 AC: 94 AN: 68006

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00196 Hom.: 0

Bravo AF: 0.00158

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency (2)
-	-	1	IL12RB1-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.59
DANN	Benign	0.40
PhyloP100		-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: rs199686420; hg19: chr19-18170773;