Genetic Variant NM_001891.4:c.153C>T (chr4-69957796-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_001891.4(CSN2):c.153C>T(p.His51His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,611,658 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00094 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 4 hom. )

Consequence

CSN2
NM_001891.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.556

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 4-69957796-G-A is Benign according to our data. Variant chr4-69957796-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2654792.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.556 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSN2	NM_001891.4 link	c.153C>T	p.His51His	synonymous_variant	Exon 6 of 8	ENST00000353151.4	NP_001882.1	P05814W5RWE1
CSN2	NM_001302770.2 link	c.150C>T	p.His50His	synonymous_variant	Exon 6 of 8		NP_001289699.1	P05814
CSN2	NM_001385731.1 link	c.108C>T	p.His36His	synonymous_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.153C>T	p.His51His	synonymous_variant	Exon 6 of 8	1	NM_001891.4	ENSP00000341030.3		P05814

Frequencies

GnomAD3 genomes

AF:

0.000940

AC:

143

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00210

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00116

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00110

AC:

274

AN:

248432

Hom.:

AF XY:

0.00116

AC XY:

156

AN XY:

134426

show subpopulations

Gnomad AFR exome

AF:

0.000437

Gnomad AMR exome

AF:

0.00111

Gnomad ASJ exome

AF:

0.00121

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000624

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.00159

Gnomad OTH exome

AF:

0.00315

GnomAD4 exome

AF:

0.00101

AC:

1480

AN:

1459424

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

752

AN XY:

725614

show subpopulations

Gnomad4 AFR exome

AF:

0.000749

Gnomad4 AMR exome

AF:

0.00124

Gnomad4 ASJ exome

AF:

0.00108

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000871

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000984

Gnomad4 OTH exome

AF:

0.00202

GnomAD4 genome

AF:

0.000939

AC:

143

AN:

152234

Hom.:

Cov.:

AF XY:

0.000981

AC XY:

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.000505

Gnomad4 AMR

AF:

0.00210

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00116

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00135

Hom.:

Bravo

AF:

0.000997

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00251

EpiControl

AF:

0.00148

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CSN2: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

2.6

DANN

Benign

0.37

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