rs2287292

Positions:

• chr2-162279752-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_022168.4(IFIH1):​c.1641+244A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 151,960 control chromosomes in the GnomAD database, including 3,775 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.14 (3775 hom., cov: 32)
• Consequence: IFIH1 NM_022168.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.477

Genes affected

IFIH1 (HGNC:18873): (interferon induced with helicase C domain 1) IFIH1 encodes MDA5 which is an intracellular sensor of viral RNA that triggers the innate immune response. Sensing RNA length and secondary structure, MDA5 binds dsRNA oligonucleotides with a modified DExD/H-box helicase core and a C-terminal domain, thus leading to a proinflammatory response that includes interferons. It has been shown that Coronaviruses (CoVs) as well as various other virus families, are capable of evading the MDA5-dependent interferon response, thus impeding the activation of the innate immune response to infection. MDA5 has also been shown to play an important role in enhancing natural killer cell function in malaria infection. In addition to its protective role in antiviral responses, MDA5 has been implicated in autoimmune and autoinflammatory diseases such as type 1 diabetes, systemic lupus erythematosus, and Aicardi-Goutieres syndrome[provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-162279752-T-G is Benign according to our data. Variant chr2-162279752-T-G is described in ClinVar as [Benign]. Clinvar id is 1228642.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFIH1	NM_022168.4	c.1641+244A>C		intron_variant		ENST00000649979.2
IFIH1	XM_047445407.1	c.924+244A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFIH1	ENST00000649979.2	c.1641+244A>C		intron_variant			NM_022168.4	P1

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21897 AN: 151840 Hom.: 3730 Cov.: 32

Gnomad AFR AF: 0.389

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.0244

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0131

Gnomad OTH AF: 0.124

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.145 AC: 22016 AN: 151960 Hom.: 3775 Cov.: 32 AF XY: 0.145 AC XY: 10736 AN XY: 74278

Gnomad4 AFR AF: 0.390

Gnomad4 AMR AF: 0.248

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.123

Gnomad4 SAS AF: 0.0243

Gnomad4 FIN AF: 0.0120

Gnomad4 NFE AF: 0.0130

Gnomad4 OTH AF: 0.130

Alfa AF: 0.0919 Hom.: 283

Bravo AF: 0.179

Asia WGS AF: 0.127 AC: 441 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.13
DANN	Benign	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: rs2287292; hg19: chr2-163136262;