7-22731419-A-T

Position:

• chr7-22731419-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000600.5(IL6):​c.485A>T​(p.Asp162Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00741 in 1,573,798 control chromosomes in the GnomAD database, including 58 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D162E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0055 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0076 (53 hom.)
• Consequence: IL6 NM_000600.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.193

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041643977).
• BP6: Variant 7-22731419-A-T is Benign according to our data. Variant chr7-22731419-A-T is described in ClinVar as [Benign]. Clinvar id is 777811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 835 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL6	NM_000600.5	c.485A>T	p.Asp162Val	missense_variant	5/5	ENST00000258743.10	NP_000591.1
IL6	NM_001371096.1	c.416A>T	p.Asp139Val	missense_variant	5/5		NP_001358025.1
IL6	NM_001318095.2	c.257A>T	p.Asp86Val	missense_variant	4/4		NP_001305024.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL6	ENST00000258743.10	c.485A>T	p.Asp162Val	missense_variant	5/5	1	NM_000600.5	ENSP00000258743.5

Frequencies

GnomAD3 genomes AF: 0.00548 AC: 834 AN: 152158 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.00641

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00844

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00597 AC: 1404 AN: 235312 Hom.: 10 AF XY: 0.00656 AC XY: 839 AN XY: 127898

Gnomad AFR exome AF: 0.00138

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.000557

Gnomad EAS exome AF: 0.000174

Gnomad SAS exome AF: 0.0111

Gnomad FIN exome AF: 0.00743

Gnomad NFE exome AF: 0.00757

Gnomad OTH exome AF: 0.00631

GnomAD4 exome AF: 0.00762 AC: 10831 AN: 1421522 Hom.: 53 Cov.: 30 AF XY: 0.00769 AC XY: 5416 AN XY: 704344

Gnomad4 AFR exome AF: 0.000869

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.000281

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.0102

Gnomad4 FIN exome AF: 0.00796

Gnomad4 NFE exome AF: 0.00832

Gnomad4 OTH exome AF: 0.00722

GnomAD4 genome AF: 0.00548 AC: 835 AN: 152276 Hom.: 5 Cov.: 31 AF XY: 0.00576 AC XY: 429 AN XY: 74458

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0122

Gnomad4 FIN AF: 0.00641

Gnomad4 NFE AF: 0.00844

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00713 Hom.: 5

Bravo AF: 0.00483

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00814 AC: 70

ExAC AF: 0.00612 AC: 743

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	IL6: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.9
DANN	Benign	0.50
DEOGEN2	Benign	0.22	T;T;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.68	.;T;T;T
MetaRNN	Benign	0.0042	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.28	N;N;.;.
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Benign	0.020
Sift	Benign	0.12	T;T;T;T
Sift4G	Benign	0.083	T;T;T;T
Polyphen		0.0080	B;B;.;.
Vest4		0.17
MVP		0.25
MPC		0.25
ClinPred		0.0059	T
GERP RS		0.44
Varity_R		0.53
gMVP		0.34

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

Other links and lift over

dbSNP: rs2069860; hg19: chr7-22771038; COSMIC: COSV99033920; COSMIC: COSV99033920;