19-1271598-G-C

Position:

• chr19-1271598-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001300829.2(CIRBP):​c.397G>C​(p.Gly133Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CIRBP NM_001300829.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.45

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23273683).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CIRBP	NM_001300829.2	c.397G>C	p.Gly133Arg	missense_variant	5/6	ENST00000587896.6	NP_001287758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CIRBP	ENST00000587896.6	c.397G>C	p.Gly133Arg	missense_variant	5/6	2	NM_001300829.2	ENSP00000466025.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152064 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74272

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

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

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

Aug 13, 2021

The c.397G>C (p.G133R) alteration is located in exon 5 (coding exon 4) of the CIRBP gene. This alteration results from a G to C substitution at nucleotide position 397, causing the glycine (G) at amino acid position 133 to be replaced by an arginine (R). 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	Pathogenic	0.60
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T;T;T;.;T;T;T;T;.;T;.;T;.;T;T;.
Eigen	Benign	-0.021
Eigen_PC	Benign	0.029
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	.;.;.;.;D;.;.;D;.;.;D;.;T;.;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.9	M;M;M;.;.;M;.;.;.;.;.;.;.;.;M;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.7	.;.;.;.;.;.;.;.;.;.;.;.;N;.;N;.
REVEL	Benign	0.13
Sift	Benign	0.038	.;.;.;.;.;.;.;.;.;.;.;.;D;.;T;.
Sift4G	Uncertain	0.044	D;D;D;T;T;D;D;D;T;D;D;D;D;D;D;T
Polyphen		0.020	B;B;B;.;.;B;P;P;.;P;.;P;.;P;B;.
Vest4		0.49
MutPred		0.31		Gain of methylation at G133 (P = 0.0145);Gain of methylation at G133 (P = 0.0145);Gain of methylation at G133 (P = 0.0145);Gain of methylation at G133 (P = 0.0145);Gain of methylation at G133 (P = 0.0145);Gain of methylation at G133 (P = 0.0145);Gain of methylation at G133 (P = 0.0145);Gain of methylation at G133 (P = 0.0145);Gain of methylation at G133 (P = 0.0145);Gain of methylation at G133 (P = 0.0145);Gain of methylation at G133 (P = 0.0145);Gain of methylation at G133 (P = 0.0145);.;Gain of methylation at G133 (P = 0.0145);Gain of methylation at G133 (P = 0.0145);Gain of methylation at G133 (P = 0.0145);
MVP		0.73
MPC		0.78
ClinPred		0.96	D
GERP RS		3.2
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.0
Varity_R		0.14
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1220292326; hg19: chr19-1271597;