Genetic Variant CIRBP:p.Arg154Trp (chr19-1272009-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001300829.2(CIRBP):c.460C>T(p.Arg154Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000931 in 1,611,914 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

CIRBP
NM_001300829.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.61

Variant links:

Genes affected

CIRBP (HGNC:1982): (cold inducible RNA binding protein) Enables mRNA 3'-UTR binding activity and small ribosomal subunit rRNA binding activity. Involved in mRNA stabilization; positive regulation of translation; and response to UV. Located in cytoplasm and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

CIRBP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIRBP	NM_001300829.2 link	c.460C>T	p.Arg154Trp	missense_variant	Exon 6 of 6	ENST00000587896.6	NP_001287758.1	Q14011D6W5Y5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIRBP	ENST00000587896.6 link	c.460C>T	p.Arg154Trp	missense_variant	Exon 6 of 6	2	NM_001300829.2	ENSP00000466025.1		D6W5Y5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250694

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135582

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000959

AC:

AN:

1459776

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

725722

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000991

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.460C>T (p.R154W) alteration is located in exon 6 (coding exon 5) of the CIRBP gene. This alteration results from a C to T substitution at nucleotide position 460, causing the arginine (R) at amino acid position 154 to be replaced by a tryptophan (W). 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

Uncertain

0.46

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;T;T;.;T;T;T;T;.;T;T;.;T;T;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.98

.;.;.;.;D;.;.;D;.;.;.;D;.;D;D

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.47

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.7

M;M;M;.;.;M;.;.;.;.;.;.;.;M;.

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.8

.;.;.;.;.;.;.;.;.;.;.;D;.;D;.

REVEL

Benign

0.16

Sift

Pathogenic

0.0

.;.;.;.;.;.;.;.;.;.;.;D;.;D;.

Sift4G

Benign

0.17

T;T;T;T;T;T;D;D;T;D;D;D;D;T;T

Polyphen

0.0020

B;B;B;.;.;B;B;B;.;B;B;.;B;B;.

Vest4

0.76

MutPred

0.36

Loss of MoRF binding (P = 0.0962);Loss of MoRF binding (P = 0.0962);Loss of MoRF binding (P = 0.0962);Loss of MoRF binding (P = 0.0962);Loss of MoRF binding (P = 0.0962);Loss of MoRF binding (P = 0.0962);Loss of MoRF binding (P = 0.0962);Loss of MoRF binding (P = 0.0962);Loss of MoRF binding (P = 0.0962);Loss of MoRF binding (P = 0.0962);Loss of MoRF binding (P = 0.0962);.;Loss of MoRF binding (P = 0.0962);Loss of MoRF binding (P = 0.0962);Loss of MoRF binding (P = 0.0962);

MVP

0.69

MPC

0.68

ClinPred

0.98

GERP RS

0.65

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.7

Varity_R

0.35

gMVP

0.71

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over