Genetic Variant IL6:p.Phe201Phe (chr7-22731537-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_000600.5(IL6):c.603C>T(p.Phe201Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0328 in 1,605,788 control chromosomes in the GnomAD database, including 1,687 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.060 ( 540 hom., cov: 31)

Exomes 𝑓: 0.030 ( 1147 hom. )

Consequence

IL6
NM_000600.5 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.748

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 7-22731537-C-T is Benign according to our data. Variant chr7-22731537-C-T is described in ClinVar as [Benign]. Clinvar id is 3056054.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=0.748 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL6	NM_000600.5 link	c.603C>T	p.Phe201Phe	synonymous_variant	Exon 5 of 5	ENST00000258743.10	NP_000591.1	P05231Q75MH2B4DVM1
IL6	NM_001371096.1 link	c.534C>T	p.Phe178Phe	synonymous_variant	Exon 5 of 5		NP_001358025.1
IL6	NM_001318095.2 link	c.375C>T	p.Phe125Phe	synonymous_variant	Exon 4 of 4		NP_001305024.1	B5MC21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL6	ENST00000258743.10 link	c.603C>T	p.Phe201Phe	synonymous_variant	Exon 5 of 5	1	NM_000600.5	ENSP00000258743.5		P05231

Frequencies

GnomAD3 genomes

AF:

0.0600

AC:

9134

AN:

152112

Hom.:

539

Cov.:

show subpopulations

Gnomad AFR

AF:

0.144

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0520

Gnomad ASJ

AF:

0.0714

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.0575

Gnomad FIN

AF:

0.0220

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0221

Gnomad OTH

AF:

0.0513

GnomAD3 exomes

AF:

0.0436

AC:

10870

AN:

249434

Hom.:

446

AF XY:

0.0409

AC XY:

5518

AN XY:

134846

show subpopulations

Gnomad AFR exome

AF:

0.148

Gnomad AMR exome

AF:

0.0774

Gnomad ASJ exome

AF:

0.0718

Gnomad EAS exome

AF:

0.00181

Gnomad SAS exome

AF:

0.0555

Gnomad FIN exome

AF:

0.0227

Gnomad NFE exome

AF:

0.0239

Gnomad OTH exome

AF:

0.0374

GnomAD4 exome

AF:

0.0299

AC:

43489

AN:

1453558

Hom.:

1147

Cov.:

AF XY:

0.0299

AC XY:

21616

AN XY:

722728

show subpopulations

Gnomad4 AFR exome

AF:

0.153

Gnomad4 AMR exome

AF:

0.0748

Gnomad4 ASJ exome

AF:

0.0721

Gnomad4 EAS exome

AF:

0.000884

Gnomad4 SAS exome

AF:

0.0549

Gnomad4 FIN exome

AF:

0.0217

Gnomad4 NFE exome

AF:

0.0226

Gnomad4 OTH exome

AF:

0.0357

GnomAD4 genome

AF:

0.0601

AC:

9149

AN:

152230

Hom.:

540

Cov.:

AF XY:

0.0594

AC XY:

4424

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.144

Gnomad4 AMR

AF:

0.0524

Gnomad4 ASJ

AF:

0.0714

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.0574

Gnomad4 FIN

AF:

0.0220

Gnomad4 NFE

AF:

0.0220

Gnomad4 OTH

AF:

0.0503

Alfa

AF:

0.0323

Hom.:

221

Bravo

AF:

0.0677

Asia WGS

AF:

0.0350

AC:

121

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

IL6-related disorder

Benign:1

Oct 24, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

7.8

DANN

Benign

0.59

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