4-69957275-C-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001891.4(CSN2):c.674G>C(p.Ser225Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000202 in 1,538,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

CSN2
NM_001891.4 missense, splice_region

Scores

Splicing: ADA: 0.00003549

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.35

Variant links:

Genes affected

CSN2 (HGNC:2447): (casein beta) This gene is a member of the beta casein family. There are two types of casein protein, beta (encoded by this gene) and kappa, both of which are secreted in human milk. Beta casein is the principal protein in human milk and the primary source of essential amino acids for a suckling infant. Beta and kappa casein proteins acting together form spherical micelles which bind within them important dietary minerals, such as calcium and phosphorous. In addition, the C-terminal 14 aa of the protein has antimicrobial activity, especially in preterm milk, displaying antibacterial activity against S. aureus and Y. enterocolitica. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2020]

CSN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.017617017).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSN2	NM_001891.4 link	c.674G>C	p.Ser225Thr	missense_variant, splice_region_variant	Exon 6 of 8	ENST00000353151.4	NP_001882.1	P05814W5RWE1
CSN2	NM_001302770.2 link	c.671G>C	p.Ser224Thr	missense_variant, splice_region_variant	Exon 6 of 8		NP_001289699.1	P05814
CSN2	NM_001385731.1 link	c.629G>C	p.Ser210Thr	missense_variant, splice_region_variant	Exon 5 of 7		NP_001372660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSN2	ENST00000353151.4 link	c.674G>C	p.Ser225Thr	missense_variant, splice_region_variant	Exon 6 of 8	1	NM_001891.4	ENSP00000341030.3		P05814

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152078

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:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000405

AC:

AN:

197428

Hom.:

AF XY:

0.0000765

AC XY:

AN XY:

104614

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:

0.000441

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000209

AC:

AN:

1386136

Hom.:

Cov.:

AF XY:

0.0000309

AC XY:

AN XY:

680632

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:

0.000382

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000175

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000660

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.674G>C (p.S225T) alteration is located in exon 5 (coding exon 5) of the CSN2 gene. This alteration results from a G to C substitution at nucleotide position 674, causing the serine (S) at amino acid position 225 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

0.076

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.0020

DANN

Benign

0.25

DEOGEN2

Benign

0.24

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0041

M_CAP

Benign

0.0017

MetaRNN

Benign

0.018

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.25

PROVEAN

Benign

0.15

REVEL

Benign

0.019

Sift

Benign

0.96

Sift4G

Benign

0.93

Polyphen

0.0

Vest4

0.16

MutPred

0.12

Loss of glycosylation at S225 (P = 0.025);

MVP

0.12

MPC

0.0018

ClinPred

0.022

GERP RS

-8.5

Varity_R

0.034

gMVP

0.084

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000035

dbscSNV1_RF

Benign

0.0060

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