chr10-89306581-C-A

Position:

• chr10-89306581-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001547.5(IFIT2):​c.625C>A​(p.Gln209Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFIT2 NM_001547.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.148

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:):

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06805673).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFIT2	NM_001547.5	c.625C>A	p.Gln209Lys	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.625C>A	p.Gln209Lys	missense_variant	2/2	1	NM_001547.5	ENSP00000360891.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2022

The c.625C>A (p.Q209K) alteration is located in exon 2 (coding exon 2) of the IFIT2 gene. This alteration results from a C to A substitution at nucleotide position 625, causing the glutamine (Q) at amino acid position 209 to be replaced by a lysine (K). 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	0.17
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
DANN	Benign	0.79
DEOGEN2	Benign	0.032	T;T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.62	.;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.068	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.6	M;M;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.7	.;N;.
REVEL	Benign	0.11
Sift	Benign	0.92	.;T;.
Sift4G	Benign	0.69	.;T;T
Polyphen		0.27	B;B;.
Vest4		0.18, 0.17
MutPred		0.39		Gain of MoRF binding (P = 0.0365);Gain of MoRF binding (P = 0.0365);Gain of MoRF binding (P = 0.0365);
MVP		0.38
MPC		0.24
ClinPred		0.086	T
GERP RS		2.5
Varity_R		0.14
gMVP		0.31

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: rs201969228; hg19: chr10-91066338; COSMIC: COSV51078707;