14-92155227-G-T

Variant names:

• chr14-92155227-G-T
• rs761607995
• NM_017437.3:c.1346G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017437.3(CPSF2):​c.1346G>T​(p.Arg449Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,718 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R449H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CPSF2 NM_017437.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.74
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017437.3. 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.1346G>T	p.Arg449Leu	missense	Exon 11 of 16	NP_059133.1	Q9P2I0
	CPSF2	NM_001322272.2		c.1346G>T	p.Arg449Leu	missense	Exon 11 of 16	NP_001309201.1	Q9P2I0
	CPSF2	NM_001322270.2		c.1346G>T	p.Arg449Leu	missense	Exon 11 of 15	NP_001309199.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPSF2	ENST00000298875.9	TSL:1 MANE Select	c.1346G>T	p.Arg449Leu	missense	Exon 11 of 16	ENSP00000298875.4	Q9P2I0
	CPSF2	ENST00000908829.1		c.1346G>T	p.Arg449Leu	missense	Exon 11 of 16	ENSP00000578888.1
	CPSF2	ENST00000932645.1		c.1346G>T	p.Arg449Leu	missense	Exon 12 of 17	ENSP00000602704.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461718 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727154

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111884

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.2	L
PhyloP100		9.7
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.38
Sift	Benign	0.17	T
Sift4G	Benign	0.63	T
Polyphen		0.53	P
Vest4		0.91
MutPred		0.42		Gain of ubiquitination at K444 (P = 0.0249)
MVP		0.65
MPC		0.78
ClinPred		0.92	D
GERP RS		5.8
PromoterAI		-0.034	Neutral
Varity_R		0.29
gMVP		0.55
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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

dbSNP: rs761607995; hg19: chr14-92621571;