4-70249130-C-T

Variant summary

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

The NM_001394997.1(CSN3):​c.220C>T​(p.Pro74Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,754 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 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: 6.8e-7 ( 0 hom. )

Consequence

CSN3
NM_001394997.1 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.68
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
CSN3NM_001394997.1 linkc.220C>T p.Pro74Ser missense_variant Exon 4 of 5 ENST00000304954.4 NP_001381926.1
CSN3NM_005212.3 linkc.220C>T p.Pro74Ser missense_variant Exon 5 of 6 NP_005203.2 P07498
CSN3XM_017007761.2 linkc.220C>T p.Pro74Ser missense_variant Exon 4 of 5 XP_016863250.1 P07498

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CSN3ENST00000304954.4 linkc.220C>T p.Pro74Ser missense_variant Exon 4 of 5 1 NM_001394997.1 ENSP00000304822.3 P07498
CSN3ENST00000689459.1 linkc.220C>T p.Pro74Ser missense_variant Exon 4 of 5 ENSP00000508633.1 P07498

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250712
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135468
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000884
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461754
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727176
show subpopulations
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 25, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.220C>T (p.P74S) alteration is located in exon 4 (coding exon 3) of the CSN3 gene. This alteration results from a C to T substitution at nucleotide position 220, causing the proline (P) at amino acid position 74 to be replaced by a serine (S). 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
0.18
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Benign
0.10
T
Eigen
Uncertain
0.24
Eigen_PC
Benign
0.16
FATHMM_MKL
Benign
0.70
D
LIST_S2
Benign
0.44
T
M_CAP
Benign
0.0069
T
MetaRNN
Uncertain
0.48
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.3
L
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-1.8
N
REVEL
Benign
0.11
Sift
Benign
0.10
T
Sift4G
Benign
0.64
T
Polyphen
0.99
D
Vest4
0.25
MutPred
0.68
Loss of stability (P = 0.0158);
MVP
0.64
MPC
0.23
ClinPred
0.33
T
GERP RS
4.4
Varity_R
0.066
gMVP
0.20

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.

Other links and lift over

dbSNP: rs746268983; hg19: chr4-71114847; COSMIC: COSV59243925; API