7-22727515-C-A

Position:

chr7-22727515-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 13/20 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, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0100

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 made for transcript

Verdict is Benign. Variant got -20 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 id is 709119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1105 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL6	NM_000600.5 linkuse as main transcript	c.91C>A	p.Pro31Thr	missense_variant	2/5	ENST00000258743.10
IL6-AS1	NR_131935.1 linkuse as main transcript	n.53+53G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL6	ENST00000258743.10 linkuse as main transcript	c.91C>A	p.Pro31Thr	missense_variant	2/5	1	NM_000600.5	P1
IL6-AS1	ENST00000325042.2 linkuse as main transcript	n.53+53G>T		intron_variant, non_coding_transcript_variant		1

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

GnomAD3 exomes

AF:

0.00168

AC:

421

AN:

250298

Hom.:

AF XY:

0.00125

AC XY:

169

AN XY:

135276

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 SAS exome

AF:

0.000196

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

Gnomad4 AFR exome

AF:

0.0225

Gnomad4 AMR exome

AF:

0.00107

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000630

Gnomad4 OTH exome

AF:

0.00172

GnomAD4 genome

AF:

0.00725

AC:

1105

AN:

152318

Hom.:

Cov.:

AF XY:

0.00708

AC XY:

527

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0249

Gnomad4 AMR

AF:

0.00288

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.00114

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

IL6-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 29, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.36

CADD

Benign

7.6

DANN

Benign

0.77

DEOGEN2

Benign

0.17

T;T;T;T;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.017

MetaRNN

Benign

0.0035

T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.5

L;.;L;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

-2.2

N;D;N;N;N

REVEL

Benign

0.084

Sift

Benign

0.77

T;T;T;D;T

Sift4G

Benign

0.28

T;T;T;T;T

Polyphen

0.0090

B;.;B;.;B

Vest4

0.075

MVP

0.77

MPC

0.19

ClinPred

0.019

GERP RS

0.89

Varity_R

0.040

gMVP

0.30

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over