NM_024496.4:c.2141G>C

Variant names:

• chr14-77025652-C-G
• rs370752093
• NM_024496.4:c.2141G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3 BS1_Supporting BS2

The NM_024496.4(IRF2BPL):​c.2141G>C​(p.Cys714Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000035 in 1,569,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: IRF2BPL NM_024496.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.14
• Publications: 0 publications found

Genes affected

IRF2BPL (HGNC:14282): (interferon regulatory factor 2 binding protein like) This gene encodes a transcription factor that may play a role in regulating female reproductive function. [provided by RefSeq, Jun 2012]

LINC02289 (HGNC:53205): (long intergenic non-protein coding RNA 2289)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000263 (4/152188) while in subpopulation NFE AF = 0.0000441 (3/68030). AF 95% confidence interval is 0.0000117. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 51 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024496.4. 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
	IRF2BPL	NM_024496.4	MANE Select	c.2141G>C	p.Cys714Ser	missense	Exon 1 of 1	NP_078772.1	Q9H1B7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF2BPL	ENST00000238647.5	TSL:6 MANE Select	c.2141G>C	p.Cys714Ser	missense	Exon 1 of 1	ENSP00000238647.3	Q9H1B7
	LINC02289	ENST00000716908.1		n.304+15402G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000460 AC: 1 AN: 217450 AF XY: 0.00

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: 0.0000102

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000360 AC: 51 AN: 1417748 Hom.: 0 Cov.: 31 AF XY: 0.0000357 AC XY: 25 AN XY: 699606

African (AFR) AF: 0.00 AC: 0 AN: 32460

American (AMR) AF: 0.00 AC: 0 AN: 40960

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22996

East Asian (EAS) AF: 0.00 AC: 0 AN: 39264

South Asian (SAS) AF: 0.00 AC: 0 AN: 79332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51674

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5552

European-Non Finnish (NFE) AF: 0.0000423 AC: 46 AN: 1087066

Other (OTH) AF: 0.0000856 AC: 5 AN: 58444

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74336

African (AFR) AF: 0.0000241 AC: 1 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.1
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Uncertain	0.39
Sift	Benign	0.045	D
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.83
MutPred		0.27		Gain of glycosylation at C714 (P = 0.0136)
MVP		0.27
MPC		1.0
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.79
gMVP		0.79
Mutation Taster		=49/51	disease causing

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: rs370752093; hg19: chr14-77491995;