Genetic Variant IL6:p.Pro31Thr (chr7-22727515-C-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_000600.5(IL6):c.91C>A(p.Pro31Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,613,972 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0073 ( 16 hom., cov: 32)

Exomes 𝑓: 0.00068 ( 11 hom. )

Consequence

IL6
NM_000600.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.0100

Publications

13 publications found

Variant links:

Genes affected

IL6 (HGNC:6018): (interleukin 6) This gene encodes a cytokine that functions in inflammation and the maturation of B cells. In addition, the encoded protein has been shown to be an endogenous pyrogen capable of inducing fever in people with autoimmune diseases or infections. The protein is primarily produced at sites of acute and chronic inflammation, where it is secreted into the serum and induces a transcriptional inflammatory response through interleukin 6 receptor, alpha. The functioning of this gene is implicated in a wide variety of inflammation-associated disease states, including suspectibility to diabetes mellitus and systemic juvenile rheumatoid arthritis. Elevated levels of the encoded protein have been found in virus infections, including COVID-19 (disease caused by SARS-CoV-2). [provided by RefSeq, Aug 2020]

IL6 links:

IL6-AS1 (HGNC:40301): (IL6 antisense RNA 1)

IL6-AS1 links:

STEAP1B (HGNC:41907): (STEAP family member 1B) Predicted to be integral component of membrane. Predicted to be active in endosome and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

STEAP1B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0035251975).

BP6

Variant 7-22727515-C-A is Benign according to our data. Variant chr7-22727515-C-A is described in ClinVar as Benign. ClinVar VariationId is 709119.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00725 (1105/152318) while in subpopulation AFR AF = 0.0249 (1037/41564). AF 95% confidence interval is 0.0237. There are 16 homozygotes in GnomAd4. There are 527 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1105 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000600.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL6	NM_000600.5	MANE Select	c.91C>A	p.Pro31Thr	missense	Exon 2 of 5	NP_000591.1	P05231
IL6	NM_001371096.1		c.22C>A	p.Pro8Thr	missense splice_region	Exon 2 of 5	NP_001358025.1	B5MCZ3
IL6	NM_001318095.2		c.-19+234C>A		intron	N/A	NP_001305024.1	B5MC21

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL6	ENST00000258743.10	TSL:1 MANE Select	c.91C>A	p.Pro31Thr	missense	Exon 2 of 5	ENSP00000258743.5	P05231
IL6	ENST00000485300.1	TSL:1	c.253C>A	p.Pro85Thr	missense	Exon 1 of 4	ENSP00000512964.1	A0A8Q3SJL1
IL6-AS1	ENST00000325042.2	TSL:1	n.53+53G>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00723

AC:

1101

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0249

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00168

AC:

421

AN:

250298

AF XY:

0.00125

show subpopulations

Gnomad AFR exome

AF:

0.0229

Gnomad AMR exome

AF:

0.000956

Gnomad ASJ exome

AF:

0.0000997

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000620

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000682

AC:

997

AN:

1461654

Hom.:

Cov.:

AF XY:

0.000612

AC XY:

445

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.0225

AC:

754

AN:

33476

American (AMR)

AF:

0.00107

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000151

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000630

AC:

AN:

1111910

Other (OTH)

AF:

0.00172

AC:

104

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

112

169

225

281

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00725

AC:

1105

AN:

152318

Hom.:

Cov.:

AF XY:

0.00708

AC XY:

527

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0249

AC:

1037

AN:

41564

American (AMR)

AF:

0.00288

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68036

Other (OTH)

AF:

0.00615

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

120

180

240

300

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00263

Hom.:

Bravo

AF:

0.00781

ESP6500AA

AF:

0.0259

AC:

114

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00209

AC:

254

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

IL6-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.36

CADD

Benign

7.6

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.17

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0035

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.5

PhyloP100

-0.010

PrimateAI

Benign

0.22

PROVEAN

Benign

-2.2

REVEL

Benign

0.084

Sift

Benign

0.77

Sift4G

Benign

0.28

Polyphen

0.0090

Vest4

0.075

MVP

0.77

MPC

0.19

ClinPred

0.019

GERP RS

0.89

PromoterAI

-0.0026

Neutral

(source)

Varity_R

0.040

gMVP

0.30

Mutation Taster

=99/1

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over