2-219172873-G-T

Variant names:

• chr2-219172873-G-T
• rs371481623
• NM_015680.6:c.946C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015680.6(CNPPD1):​c.946C>A​(p.Leu316Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNPPD1 NM_015680.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.11

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17054689).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNPPD1	NM_015680.6	c.946C>A	p.Leu316Met	missense_variant	Exon 8 of 8	ENST00000360507.10	NP_056495.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNPPD1	ENST00000360507.10	c.946C>A	p.Leu316Met	missense_variant	Exon 8 of 8	1	NM_015680.6	ENSP00000353698.5
CNPPD1	ENST00000409789.5	c.946C>A	p.Leu316Met	missense_variant	Exon 9 of 9	1		ENSP00000386277.1
CNPPD1	ENST00000453038.5	c.*21C>A		downstream_gene_variant		2		ENSP00000410109.1
CNPPD1	ENST00000451647.1	c.*178C>A		downstream_gene_variant		3		ENSP00000405997.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000423 AC: 1 AN: 236656 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 127296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 60

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.946C>A (p.L316M) alteration is located in exon 8 (coding exon 8) of the CNPPD1 gene. This alteration results from a C to A substitution at nucleotide position 946, causing the leucine (L) at amino acid position 316 to be replaced by a methionine (M). 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	0.11
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0035	T;T
Eigen	Benign	0.0041
Eigen_PC	Benign	-0.047
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.65	.;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L;L
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.69	N;N
REVEL	Benign	0.074
Sift	Benign	0.11	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.98	D;D
Vest4		0.26
MutPred		0.13		Loss of glycosylation at S315 (P = 0.0484);Loss of glycosylation at S315 (P = 0.0484);
MVP		0.36
MPC		0.71
ClinPred		0.37	T
GERP RS		0.95
Varity_R		0.060
gMVP		0.39

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: rs371481623; hg19: chr2-220037595;