chr5-2748895-C-G

Variant names:

• chr5-2748895-C-G
• NM_033267.5:c.813G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033267.5(IRX2):​c.813G>C​(p.Glu271Asp) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IRX2 NM_033267.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.45
• Publications: 0 publications found

Genes affected

IRX2 (HGNC:14359): (iroquois homeobox 2) IRX2 is a member of the Iroquois homeobox gene family. Members of this family appear to play multiple roles during pattern formation of vertebrate embryos.[supplied by OMIM, Apr 2004]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050784916).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRX2	NM_033267.5	c.813G>C	p.Glu271Asp	missense_variant	Exon 3 of 4	ENST00000302057.6	NP_150366.1
IRX2	NM_001134222.2	c.813G>C	p.Glu271Asp	missense_variant	Exon 3 of 5		NP_001127694.1
IRX2	XM_011513979.3	c.813G>C	p.Glu271Asp	missense_variant	Exon 3 of 5		XP_011512281.1
IRX2	XM_024454379.2	c.534G>C	p.Glu178Asp	missense_variant	Exon 3 of 4		XP_024310147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRX2	ENST00000302057.6	c.813G>C	p.Glu271Asp	missense_variant	Exon 3 of 4	1	NM_033267.5	ENSP00000307006.5
IRX2	ENST00000382611.10	c.813G>C	p.Glu271Asp	missense_variant	Exon 3 of 5	1		ENSP00000372056.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.813G>C (p.E271D) alteration is located in exon 3 (coding exon 3) of the IRX2 gene. This alteration results from a G to C substitution at nucleotide position 813, causing the glutamic acid (E) at amino acid position 271 to be replaced by an aspartic acid (D). 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	0.058
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Benign	0.93
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.46	.;T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.051	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N;N
PhyloP100		-1.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.041
Sift	Benign	0.51	T;T
Sift4G	Benign	0.59	T;T
Polyphen		0.0	B;B
Vest4		0.14
MutPred		0.28		Gain of catalytic residue at G273 (P = 0.4231);Gain of catalytic residue at G273 (P = 0.4231);
MVP		0.45
MPC		0.39
ClinPred		0.059	T
GERP RS		2.7
Varity_R		0.12
gMVP		0.087
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

hg19: chr5-2749009;