Variant 14-92143251-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_017437.3(CPSF2):c.1097G>A(p.Arg366His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,610,982 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 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

CPSF2
NM_017437.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.79

Variant links:

Genes affected

CPSF2 (HGNC:2325): (cleavage and polyadenylation specific factor 2) Predicted to enable RNA binding activity. Involved in mRNA 3'-end processing by stem-loop binding activity and cleavage. Located in membrane. Part of mRNA cleavage and polyadenylation specificity factor complex. [provided by Alliance of Genome Resources, Apr 2022]

CPSF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.767

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPSF2	NM_017437.3 linkuse as main transcript	c.1097G>A	p.Arg366His	missense_variant	9/16	ENST00000298875.9	NP_059133.1	Q9P2I0A0A024R6H0
CPSF2	NM_001322272.2 linkuse as main transcript	c.1097G>A	p.Arg366His	missense_variant	9/16		NP_001309201.1	Q9P2I0A0A024R6H0
CPSF2	NM_001322270.2 linkuse as main transcript	c.1097G>A	p.Arg366His	missense_variant	9/15		NP_001309199.1
CPSF2	NM_001322271.2 linkuse as main transcript	c.638G>A	p.Arg213His	missense_variant	8/15		NP_001309200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPSF2	ENST00000298875.9 linkuse as main transcript	c.1097G>A	p.Arg366His	missense_variant	9/16	1	NM_017437.3	ENSP00000298875.4		Q9P2I0

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000845

AC:

AN:

248430

Hom.:

AF XY:

0.0000819

AC XY:

AN XY:

134282

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000503

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000329

AC:

AN:

1458870

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

725704

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000407

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2024

The c.1097G>A (p.R366H) alteration is located in exon 9 (coding exon 7) of the CPSF2 gene. This alteration results from a G to A substitution at nucleotide position 1097, causing the arginine (R) at amino acid position 366 to be replaced by a histidine (H). 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

0.56

BayesDel_addAF

Uncertain

0.058

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.039

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-0.58

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.51

Sift

Uncertain

0.014

Sift4G

Uncertain

0.021

Polyphen

1.0

Vest4

0.88

MutPred

0.51

Gain of catalytic residue at L368 (P = 0.1007);

MVP

0.76

MPC

1.6

ClinPred

0.70

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.45

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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