rs142923243

Variant names:

• chr14-92134160-A-C
• NM_017437.3:c.299A>C

Your query was ambiguous. Multiple possible variants found:

• chr14-92134160-A-C
• chr14-92134160-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_017437.3(CPSF2):​c.299A>C​(p.Asp100Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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: 9.21

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPSF2	NM_017437.3	c.299A>C	p.Asp100Ala	missense_variant	Exon 4 of 16	ENST00000298875.9	NP_059133.1
CPSF2	NM_001322272.2	c.299A>C	p.Asp100Ala	missense_variant	Exon 4 of 16		NP_001309201.1
CPSF2	NM_001322270.2	c.299A>C	p.Asp100Ala	missense_variant	Exon 4 of 15		NP_001309199.1
CPSF2	NM_001322271.2	c.-150-90A>C		intron_variant	Intron 3 of 14		NP_001309200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPSF2	ENST00000298875.9	c.299A>C	p.Asp100Ala	missense_variant	Exon 4 of 16	1	NM_017437.3	ENSP00000298875.4
CPSF2	ENST00000554290.1	n.150-90A>C		intron_variant	Intron 3 of 4	4		ENSP00000452503.1
CPSF2	ENST00000553427.5	c.*57A>C		downstream_gene_variant		4		ENSP00000451418.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461782 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.79		Gain of catalytic residue at D100 (P = 0.1295);
MVP		0.97
MPC		1.8
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr14-92600504;