7-22729515-A-G

Position:

chr7-22729515-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000600.5(IL6):c.326A>G(p.Glu109Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,612,520 control chromosomes in the GnomAD database, including 1 homozygotes. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 1 hom. )

Consequence

IL6
NM_000600.5 missense, splice_region

Scores

Splicing: ADA: 0.001633

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.13

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL6	NM_000600.5 link	c.326A>G	p.Glu109Gly	missense_variant, splice_region_variant	4/5	ENST00000258743.10	NP_000591.1	P05231Q75MH2B4DVM1
IL6	NM_001371096.1 link	c.257A>G	p.Glu86Gly	missense_variant, splice_region_variant	4/5		NP_001358025.1
IL6	NM_001318095.2 link	c.98A>G	p.Glu33Gly	missense_variant, splice_region_variant	3/4		NP_001305024.1	B5MC21
IL6	XM_005249745.6 link	c.488A>G	p.Glu163Gly	missense_variant, splice_region_variant	3/3		XP_005249802.1	B4DNQ5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL6	ENST00000258743.10 link	c.326A>G	p.Glu109Gly	missense_variant, splice_region_variant	4/5	1	NM_000600.5	ENSP00000258743.5		P05231

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250596

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135344

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1460332

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

726206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.0000189

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 17, 2024

The c.326A>G (p.E109G) alteration is located in exon 4 (coding exon 4) of the IL6 gene. This alteration results from a A to G substitution at nucleotide position 326, causing the glutamic acid (E) at amino acid position 109 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.019

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

T;T;.;T;.;T;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.86

.;D;D;D;D;D;D

M_CAP

Benign

0.047

MetaRNN

Uncertain

0.55

D;D;D;D;D;D;D

MetaSVM

Benign

-0.69

MutationAssessor

Benign

2.0

M;.;.;M;.;.;.

PrimateAI

Benign

0.33

PROVEAN

Pathogenic

-5.0

D;D;D;D;D;D;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.0030

D;D;D;D;D;D;D

Sift4G

Uncertain

0.0060

D;D;D;D;D;D;D

Polyphen

1.0

D;.;.;D;.;.;D

Vest4

0.44

MVP

0.78

MPC

0.72

ClinPred

0.96

GERP RS

4.7

Varity_R

0.52

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0016

dbscSNV1_RF

Benign

0.080

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