14-92159056-A-T

Position:

• chr14-92159056-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_017437.3(CPSF2):​c.1895A>T​(p.Asp632Val) variant causes a missense 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_017437.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.17

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPSF2	NM_017437.3	c.1895A>T	p.Asp632Val	missense_variant	14/16	ENST00000298875.9	NP_059133.1
CPSF2	NM_001322272.2	c.1895A>T	p.Asp632Val	missense_variant	14/16		NP_001309201.1
CPSF2	NM_001322270.2	c.1742A>T	p.Asp581Val	missense_variant	13/15		NP_001309199.1
CPSF2	NM_001322271.2	c.1436A>T	p.Asp479Val	missense_variant	13/15		NP_001309200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPSF2	ENST00000298875.9	c.1895A>T	p.Asp632Val	missense_variant	14/16	1	NM_017437.3	ENSP00000298875	P1
CPSF2	ENST00000555244.1	c.446A>T	p.Asp149Val	missense_variant	3/4	3		ENSP00000451390

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

May 24, 2023

The c.1895A>T (p.D632V) alteration is located in exon 14 (coding exon 12) of the CPSF2 gene. This alteration results from a A to T substitution at nucleotide position 1895, causing the aspartic acid (D) at amino acid position 632 to be replaced by a valine (V). 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	0.97
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.32	T
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.97	D
Vest4		0.94
MutPred		0.73		Loss of sheet (P = 0.0104);
MVP		0.75
MPC		1.9
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.80
gMVP		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-92625400;