chr2-219172935-A-T

Position:

• chr2-219172935-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000360507.10(CNPPD1):​c.884T>A​(p.Val295Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,374 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CNPPD1 ENST00000360507.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.44

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]

ACMG classification

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=0.04164508).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNPPD1	NM_015680.6	c.884T>A	p.Val295Asp	missense_variant	8/8	ENST00000360507.10	NP_056495.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNPPD1	ENST00000360507.10	c.884T>A	p.Val295Asp	missense_variant	8/8	1	NM_015680.6	ENSP00000353698	P1
CNPPD1	ENST00000409789.5	c.884T>A	p.Val295Asp	missense_variant	9/9	1		ENSP00000386277	P1
CNPPD1	ENST00000453038.5	c.884T>A	p.Val295Asp	missense_variant	9/9	2		ENSP00000410109

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461374 Hom.: 0 Cov.: 59 AF XY: 0.00 AC XY: 0 AN XY: 726994

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

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 13, 2024

The c.884T>A (p.V295D) alteration is located in exon 8 (coding exon 8) of the CNPPD1 gene. This alteration results from a T to A substitution at nucleotide position 884, causing the valine (V) at amino acid position 295 to be replaced by an aspartic acid (D). 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	0.10
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	13
DANN	Benign	0.81
DEOGEN2	Benign	0.0015	T;T;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.75	.;T;T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.042	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.69	N;N;.
MutationTaster	Benign	0.56	D;D
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.27	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.60	T;T;D
Sift4G	Benign	0.63	T;T;.
Polyphen		0.079	B;B;.
Vest4		0.19
MutPred		0.14		Loss of catalytic residue at N294 (P = 0.1428);Loss of catalytic residue at N294 (P = 0.1428);Loss of catalytic residue at N294 (P = 0.1428);
MVP		0.17
MPC		0.40
ClinPred		0.065	T
GERP RS		1.4
Varity_R		0.13
gMVP		0.32

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

Other links and lift over

dbSNP: rs1950096846; hg19: chr2-220037657; COSMIC: COSV99041305; COSMIC: COSV99041305;