dbSNP rs2070845: IFIT2:p.Lys121Arg (chr10-89306318-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001547.5(IFIT2):c.362A>G(p.Lys121Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 1,613,760 control chromosomes in the GnomAD database, including 44,174 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.24 ( 4501 hom., cov: 32)

Exomes 𝑓: 0.23 ( 39673 hom. )

Consequence

IFIT2
NM_001547.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.88

Publications

36 publications found

Variant links:

Genes affected

IFIT2 (HGNC:5409): (interferon induced protein with tetratricopeptide repeats 2) Enables RNA binding activity. Involved in negative regulation of protein binding activity; positive regulation of apoptotic process; and response to virus. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

IFIT2 links:

LIPA (HGNC:6617): (lipase A, lysosomal acid type) This gene encodes lipase A, the lysosomal acid lipase (also known as cholesterol ester hydrolase). This enzyme functions in the lysosome to catalyze the hydrolysis of cholesteryl esters and triglycerides. Mutations in this gene can result in Wolman disease and cholesteryl ester storage disease. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2014]

LIPA Gene-Disease associations (from GenCC):

lysosomal acid lipase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
cholesteryl ester storage disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Wolman disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LIPA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033346713).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFIT2	NM_001547.5 link	c.362A>G	p.Lys121Arg	missense_variant	Exon 2 of 2	ENST00000371826.4	NP_001538.4	P09913Q05DN2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFIT2	ENST00000371826.4 link	c.362A>G	p.Lys121Arg	missense_variant	Exon 2 of 2	1	NM_001547.5	ENSP00000360891.3		P09913

Frequencies

GnomAD3 genomes

AF:

0.239

AC:

36334

AN:

151962

Hom.:

4501

Cov.:

show subpopulations

Gnomad AFR

AF:

0.266

Gnomad AMI

AF:

0.379

Gnomad AMR

AF:

0.239

Gnomad ASJ

AF:

0.270

Gnomad EAS

AF:

0.129

Gnomad SAS

AF:

0.120

Gnomad FIN

AF:

0.187

Gnomad MID

AF:

0.250

Gnomad NFE

AF:

0.244

Gnomad OTH

AF:

0.252

GnomAD2 exomes

AF:

0.212

AC:

52847

AN:

249812

AF XY:

0.207

show subpopulations

Gnomad AFR exome

AF:

0.267

Gnomad AMR exome

AF:

0.196

Gnomad ASJ exome

AF:

0.266

Gnomad EAS exome

AF:

0.121

Gnomad FIN exome

AF:

0.198

Gnomad NFE exome

AF:

0.246

Gnomad OTH exome

AF:

0.235

GnomAD4 exome

AF:

0.229

AC:

335431

AN:

1461680

Hom.:

39673

Cov.:

AF XY:

0.226

AC XY:

164273

AN XY:

727154

show subpopulations

African (AFR)

AF:

0.259

AC:

8672

AN:

33472

American (AMR)

AF:

0.198

AC:

8858

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.266

AC:

6944

AN:

26132

East Asian (EAS)

AF:

0.157

AC:

6217

AN:

39698

South Asian (SAS)

AF:

0.116

AC:

10026

AN:

86258

European-Finnish (FIN)

AF:

0.204

AC:

10897

AN:

53398

Middle Eastern (MID)

AF:

0.245

AC:

1414

AN:

5768

European-Non Finnish (NFE)

AF:

0.242

AC:

268566

AN:

1111840

Other (OTH)

AF:

0.229

AC:

13837

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

15293

30587

45880

61174

76467

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9008

18016

27024

36032

45040

<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:

0.239

AC:

36343

AN:

152080

Hom.:

4501

Cov.:

AF XY:

0.234

AC XY:

17412

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.266

AC:

11019

AN:

41478

American (AMR)

AF:

0.238

AC:

3641

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.270

AC:

937

AN:

3472

East Asian (EAS)

AF:

0.128

AC:

663

AN:

5168

South Asian (SAS)

AF:

0.119

AC:

574

AN:

4824

European-Finnish (FIN)

AF:

0.187

AC:

1983

AN:

10578

Middle Eastern (MID)

AF:

0.241

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.244

AC:

16579

AN:

67968

Other (OTH)

AF:

0.252

AC:

532

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1404

2808

4212

5616

7020

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

360

720

1080

1440

1800

<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:

0.242

Hom.:

18529

Bravo

AF:

0.246

TwinsUK

AF:

0.232

AC:

861

ALSPAC

AF:

0.239

AC:

921

ESP6500AA

AF:

0.251

AC:

1062

ESP6500EA

AF:

0.242

AC:

2063

ExAC

AF:

0.214

AC:

25933

Asia WGS

AF:

0.140

AC:

485

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

CADD

Benign

5.6

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.033

T;T;.

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.46

.;T;T

MetaRNN

Benign

0.0033

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.70

N;N;.

PhyloP100

1.9

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.2

.;N;.

REVEL

Benign

0.085

Sift

Benign

0.37

.;T;.

Sift4G

Benign

0.58

.;T;T

Polyphen

0.028

B;B;.

Vest4

0.024, 0.015

MPC

0.15

ClinPred

0.00058

GERP RS

2.2

PromoterAI

0.0054

Neutral

(source)

Varity_R

0.081

gMVP

0.11

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over