14-92134343-G-A

Variant names:

• chr14-92134343-G-A
• NM_017437.3:c.403G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001322271.2(CPSF2):​c.-57G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPSF2 NM_001322271.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.87
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001322271.2. 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
	CPSF2	NM_017437.3	MANE Select	c.403G>A	p.Val135Met	missense	Exon 5 of 16	NP_059133.1	Q9P2I0
	CPSF2	NM_001322271.2		c.-57G>A		5_prime_UTR_premature_start_codon_gain	Exon 4 of 15	NP_001309200.1
	CPSF2	NM_001322272.2		c.403G>A	p.Val135Met	missense	Exon 5 of 16	NP_001309201.1	Q9P2I0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPSF2	ENST00000298875.9	TSL:1 MANE Select	c.403G>A	p.Val135Met	missense	Exon 5 of 16	ENSP00000298875.4	Q9P2I0
	CPSF2	ENST00000908829.1		c.403G>A	p.Val135Met	missense	Exon 5 of 16	ENSP00000578888.1
	CPSF2	ENST00000932645.1		c.403G>A	p.Val135Met	missense	Exon 6 of 17	ENSP00000602704.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.59
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.15	T
Polyphen		0.98	D
Vest4		0.78
MutPred		0.47		Loss of sheet (P = 0.0315)
MVP		0.86
MPC		1.6
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.44
gMVP		0.76
Mutation Taster		=25/75	disease causing

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

Other links and lift over

hg19: chr14-92600687;