2-219172828-T-C

Position:

• chr2-219172828-T-C

Variant summary

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

The NM_015680.6(CNPPD1):​c.991A>G​(p.Thr331Ala) 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. 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: 31)
• Consequence: CNPPD1 NM_015680.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0110

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=0.032218426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNPPD1	NM_015680.6	c.991A>G	p.Thr331Ala	missense_variant	8/8	ENST00000360507.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNPPD1	ENST00000360507.10	c.991A>G	p.Thr331Ala	missense_variant	8/8	1	NM_015680.6	P1
CNPPD1	ENST00000409789.5	c.991A>G	p.Thr331Ala	missense_variant	9/9	1		P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 58

GnomAD4 genome Cov.: 31

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

Sep 16, 2022

The c.991A>G (p.T331A) alteration is located in exon 8 (coding exon 8) of the CNPPD1 gene. This alteration results from a A to G substitution at nucleotide position 991, causing the threonine (T) at amino acid position 331 to be replaced by an alanine (A). 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	0.060
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	7.4
DANN	Benign	0.78
DEOGEN2	Benign	0.0014	T;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.48	.;T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.032	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.68	N;N
REVEL	Benign	0.051
Sift	Benign	0.24	T;T
Sift4G	Benign	0.48	T;T
Polyphen		0.0	B;B
Vest4		0.049
MutPred		0.092		Loss of phosphorylation at T331 (P = 0.0279);Loss of phosphorylation at T331 (P = 0.0279);
MVP		0.12
MPC		0.23
ClinPred		0.039	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.025
gMVP		0.23

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: chr2-220037550;