rs2070845

Positions:

• chr10-89306318-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.24 (4501 hom., cov: 32)
  • Exomes 𝑓: 0.23 (39673 hom.)
• Consequence: IFIT2 NM_001547.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.88

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]

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
IFIT2	NM_001547.5	c.362A>G	p.Lys121Arg	missense_variant	2/2	ENST00000371826.4	NP_001538.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFIT2	ENST00000371826.4	c.362A>G	p.Lys121Arg	missense_variant	2/2	1	NM_001547.5	ENSP00000360891	P1

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36334 AN: 151962 Hom.: 4501 Cov.: 32

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

GnomAD3 exomes AF: 0.212 AC: 52847 AN: 249812 Hom.: 6068 AF XY: 0.207 AC XY: 28098 AN XY: 135460

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 SAS exome AF: 0.116

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.: 35 AF XY: 0.226 AC XY: 164273 AN XY: 727154

Gnomad4 AFR exome AF: 0.259

Gnomad4 AMR exome AF: 0.198

Gnomad4 ASJ exome AF: 0.266

Gnomad4 EAS exome AF: 0.157

Gnomad4 SAS exome AF: 0.116

Gnomad4 FIN exome AF: 0.204

Gnomad4 NFE exome AF: 0.242

Gnomad4 OTH exome AF: 0.229

GnomAD4 genome AF: 0.239 AC: 36343 AN: 152080 Hom.: 4501 Cov.: 32 AF XY: 0.234 AC XY: 17412 AN XY: 74346

Gnomad4 AFR AF: 0.266

Gnomad4 AMR AF: 0.238

Gnomad4 ASJ AF: 0.270

Gnomad4 EAS AF: 0.128

Gnomad4 SAS AF: 0.119

Gnomad4 FIN AF: 0.187

Gnomad4 NFE AF: 0.244

Gnomad4 OTH AF: 0.252

Alfa AF: 0.243 Hom.: 9513

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	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.6
DANN	Benign	0.79
DEOGEN2	Benign	0.033	T;T;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.46	.;T;T
MetaRNN	Benign	0.0033	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.70	N;N;.
MutationTaster	Benign	0.0000032	P;P;P;P;P
PrimateAI	Benign	0.27	T
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	T
GERP RS		2.2
Varity_R		0.081
gMVP		0.11

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

LitVar

Other links and lift over

dbSNP: rs2070845; hg19: chr10-91066075; COSMIC: COSV51079081;