2-219172744-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015680.6(CNPPD1):​c.1075G>A​(p.Val359Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,612,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CNPPD1
NM_015680.6 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.337
Variant links:
Genes affected
CNPPD1 (HGNC:25220): (cyclin Pas1/PHO80 domain containing 1) Predicted to enable cyclin-dependent protein serine/threonine kinase regulator activity. Predicted to be involved in regulation of cyclin-dependent protein serine/threonine kinase activity. Predicted to be integral component of membrane. Predicted to be part of cyclin-dependent protein kinase holoenzyme complex. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.032003343).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CNPPD1NM_015680.6 linkuse as main transcriptc.1075G>A p.Val359Ile missense_variant 8/8 ENST00000360507.10 NP_056495.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CNPPD1ENST00000360507.10 linkuse as main transcriptc.1075G>A p.Val359Ile missense_variant 8/81 NM_015680.6 ENSP00000353698 P1
CNPPD1ENST00000409789.5 linkuse as main transcriptc.1075G>A p.Val359Ile missense_variant 9/91 ENSP00000386277 P1

Frequencies

GnomAD3 genomes
AF:
0.0000855
AC:
13
AN:
151978
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000852
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000161
AC:
4
AN:
248146
Hom.:
0
AF XY:
0.00000745
AC XY:
1
AN XY:
134144
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000875
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1460318
Hom.:
0
Cov.:
59
AF XY:
0.00000138
AC XY:
1
AN XY:
726386
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000898
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000855
AC:
13
AN:
151978
Hom.:
0
Cov.:
32
AF XY:
0.000135
AC XY:
10
AN XY:
74208
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000852
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000793

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 submitterclinical testingAmbry GeneticsMar 28, 2024The c.1075G>A (p.V359I) alteration is located in exon 8 (coding exon 8) of the CNPPD1 gene. This alteration results from a G to A substitution at nucleotide position 1075, causing the valine (V) at amino acid position 359 to be replaced by an isoleucine (I). 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
Benign
0.071
BayesDel_addAF
Benign
-0.54
T
BayesDel_noAF
Benign
-0.79
CADD
Benign
0.29
DANN
Benign
0.81
DEOGEN2
Benign
0.0050
T;T
Eigen
Benign
-1.0
Eigen_PC
Benign
-0.99
FATHMM_MKL
Benign
0.079
N
LIST_S2
Benign
0.38
.;T
M_CAP
Benign
0.0033
T
MetaRNN
Benign
0.032
T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
0.90
L;L
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-0.25
N;N
REVEL
Benign
0.060
Sift
Benign
0.50
T;T
Sift4G
Benign
0.42
T;T
Polyphen
0.0
B;B
Vest4
0.034
MutPred
0.18
Loss of catalytic residue at V359 (P = 0.0595);Loss of catalytic residue at V359 (P = 0.0595);
MVP
0.12
MPC
0.19
ClinPred
0.013
T
GERP RS
0.80
Varity_R
0.016
gMVP
0.18

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1436605239; hg19: chr2-220037466; API