Genetic Variant CSN3:p.Pro67Thr (chr4-70249109-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001394997.1(CSN3):c.199C>A(p.Pro67Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

CSN3
NM_001394997.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.413

Variant links:

Genes affected

CSN3 (HGNC:2446): (casein kappa) Involved in lactation and protein stabilization. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

CSN3 links:

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ACMG classification

Classification made for transcript

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=0.07342157).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSN3	NM_001394997.1 link	c.199C>A	p.Pro67Thr	missense_variant	Exon 4 of 5	ENST00000304954.4	NP_001381926.1
CSN3	NM_005212.3 link	c.199C>A	p.Pro67Thr	missense_variant	Exon 5 of 6		NP_005203.2	P07498
CSN3	XM_017007761.2 link	c.199C>A	p.Pro67Thr	missense_variant	Exon 4 of 5		XP_016863250.1	P07498

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSN3	ENST00000304954.4 link	c.199C>A	p.Pro67Thr	missense_variant	Exon 4 of 5	1	NM_001394997.1	ENSP00000304822.3		P07498
CSN3	ENST00000689459.1 link	c.199C>A	p.Pro67Thr	missense_variant	Exon 4 of 5			ENSP00000508633.1		P07498

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

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

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.199C>A (p.P67T) alteration is located in exon 4 (coding exon 3) of the CSN3 gene. This alteration results from a C to A substitution at nucleotide position 199, causing the proline (P) at amino acid position 67 to be replaced by a threonine (T). 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

0.16

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

9.9

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.55

M_CAP

Benign

0.0055

MetaRNN

Benign

0.073

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.2

PrimateAI

Benign

0.30

PROVEAN

Benign

-2.1

REVEL

Benign

0.019

Sift

Benign

0.082

Sift4G

Benign

0.38

Polyphen

0.15

Vest4

0.25

MVP

0.26

MPC

0.23

ClinPred

0.11

GERP RS

-2.4

Varity_R

0.055

gMVP

0.36

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over