chr16-54931400-G-C

Variant names:

• chr16-54931400-G-C
• rs768213705
• NM_005853.6:c.202G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005853.6(IRX5):​c.202G>C​(p.Gly68Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,445,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G68S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IRX5 NM_005853.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.75
• Publications: 0 publications found

Genes affected

IRX5 (HGNC:14361): (iroquois homeobox 5) This gene encodes a member of the iroquois homeobox gene family, which are involved in several embryonic developmental processes. Knockout mice lacking this gene show that it is required for retinal cone bipolar cell differentiation, and that it negatively regulates potassium channel gene expression in the heart to ensure coordinated cardiac repolarization. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

CRNDE (HGNC:37078): (colorectal neoplasia differentially expressed) This gene is transcribed into multiple transcript variants, some of which may function as non-coding RNAs. One of the transcript variants encodes a putative short protein that is localized to the nucleus (PMID:25978564). Expression of this locus is increased in proliferating tissues, including certain tumors such as colorectal adenomas and adenocarcinomas. Transcription from this gene is negatively regulated by insulin and insulin-like growth factors, and may regulate the expression of genes involved in metabolism. [provided by RefSeq, May 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41375202).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005853.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRX5	NM_005853.6	MANE Select	c.202G>C	p.Gly68Arg	missense	Exon 1 of 3	NP_005844.4
	IRX5	NM_001252197.1		c.202G>C	p.Gly68Arg	missense	Exon 1 of 3	NP_001239126.1	P78411-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRX5	ENST00000394636.9	TSL:3 MANE Select	c.202G>C	p.Gly68Arg	missense	Exon 1 of 3	ENSP00000378132.4	P78411-1
	IRX5	ENST00000320990.9	TSL:1	c.202G>C	p.Gly68Arg	missense	Exon 1 of 3	ENSP00000316250.5	P78411-2
	IRX5	ENST00000967637.1		c.202G>C	p.Gly68Arg	missense	Exon 1 of 3	ENSP00000637696.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000448 AC: 1 AN: 222986 AF XY: 0.00000803

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000992

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1445076 Hom.: 0 Cov.: 32 AF XY: 0.00000278 AC XY: 2 AN XY: 719110

African (AFR) AF: 0.00 AC: 0 AN: 33206

American (AMR) AF: 0.00 AC: 0 AN: 44516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26008

East Asian (EAS) AF: 0.00 AC: 0 AN: 39550

South Asian (SAS) AF: 0.00 AC: 0 AN: 85954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4618

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109846

Other (OTH) AF: 0.0000167 AC: 1 AN: 59840

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.46	N
PhyloP100		1.8
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.25
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.032	D
Polyphen		0.63	P
Vest4		0.55
MutPred		0.24		Gain of methylation at G68 (P = 0.0394)
MVP		0.64
ClinPred		0.75	D
GERP RS		4.9
PromoterAI		-0.027	Neutral
Varity_R		0.35
gMVP		0.75
Mutation Taster		=58/42	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

dbSNP: rs768213705; hg19: chr16-54965312;