12-56314861-G-A

Variant names:

• chr12-56314861-G-A
• rs1873843456
• NM_014255.7:c.194C>T

Variant summary

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

The NM_014255.7(CNPY2):​c.194C>T​(p.Ser65Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNPY2 NM_014255.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.71

Genes affected

CNPY2 (HGNC:13529): (canopy FGF signaling regulator 2) Predicted to be active in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000144785 (HGNC:):

CNPY2-AS1 (HGNC:55480): (CNPY2 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNPY2	NM_014255.7	c.194C>T	p.Ser65Leu	missense_variant	Exon 3 of 6	ENST00000273308.9	NP_055070.1
CNPY2	NM_001190991.3	c.194C>T	p.Ser65Leu	missense_variant	Exon 3 of 3		NP_001177920.1
CNPY2-AS1	XR_002957416.2	n.*53G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNPY2	ENST00000273308.9	c.194C>T	p.Ser65Leu	missense_variant	Exon 3 of 6	1	NM_014255.7	ENSP00000273308.4
ENSG00000144785	ENST00000549318.5	c.194C>T	p.Ser65Leu	missense_variant	Exon 3 of 9	5		ENSP00000446743.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.194C>T (p.S65L) alteration is located in exon 3 (coding exon 2) of the CNPY2 gene. This alteration results from a C to T substitution at nucleotide position 194, causing the serine (S) at amino acid position 65 to be replaced by a leucine (L). 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	Uncertain	0.39
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.038	.;.;.;T;T;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.43	T;T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.6	.;.;.;M;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.5	N;N;D;N;D;N
REVEL	Benign	0.22
Sift	Benign	0.21	T;D;T;T;T;T
Sift4G	Benign	0.11	T;.;.;T;.;T
Polyphen		0.91	.;.;.;P;.;.
Vest4		0.50
MutPred		0.27		Gain of catalytic residue at P60 (P = 0.001);Gain of catalytic residue at P60 (P = 0.001);Gain of catalytic residue at P60 (P = 0.001);Gain of catalytic residue at P60 (P = 0.001);Gain of catalytic residue at P60 (P = 0.001);.;
MVP		0.64
MPC		0.42
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.34
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1873843456; hg19: chr12-56708645;