chr19-13153481-C-G

Position:

• chr19-13153481-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004907.3(IER2):​c.295C>G​(p.Gln99Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000417 in 1,437,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: IER2 NM_004907.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.15

Genes affected

IER2 (HGNC:28871): (immediate early response 2) Predicted to enable DNA binding activity. Involved in cell motility and positive regulation of transcription by RNA polymerase II. Located in cytoplasm and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0424017).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IER2	NM_004907.3	c.295C>G	p.Gln99Glu	missense_variant	2/2	ENST00000292433.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IER2	ENST00000292433.4	c.295C>G	p.Gln99Glu	missense_variant	2/2	1	NM_004907.3	P1
	ENST00000592882.1	n.629+84G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000417 AC: 6 AN: 1437712 Hom.: 0 Cov.: 31 AF XY: 0.00000561 AC XY: 4 AN XY: 713634

Gnomad4 AFR exome AF: 0.0000304

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000454

Gnomad4 OTH exome AF: 0.00

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.295C>G (p.Q99E) alteration is located in exon 2 (coding exon 1) of the IER2 gene. This alteration results from a C to G substitution at nucleotide position 295, causing the glutamine (Q) at amino acid position 99 to be replaced by a glutamic acid (E). 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	0.059
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Benign	0.014	T;T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.50	.;.;T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.042	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.63	N;N;N
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.010	.;N;.
REVEL	Benign	0.022
Sift	Benign	0.20	.;T;.
Sift4G	Benign	0.42	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.082
MutPred		0.30		Gain of phosphorylation at T98 (P = 0.1571);Gain of phosphorylation at T98 (P = 0.1571);Gain of phosphorylation at T98 (P = 0.1571);
MVP		0.043
MPC		0.47
ClinPred		0.15	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.052

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: rs1289736302; hg19: chr19-13264295;