4-69957288-G-A

Variant names:

• chr4-69957288-G-A
• NM_001891.4:c.661C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001891.4(CSN2):​c.661C>T​(p.His221Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CSN2 NM_001891.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.103

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05098155).
• BP6: Variant 4-69957288-G-A is Benign according to our data. Variant chr4-69957288-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2620447.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSN2	NM_001891.4	c.661C>T	p.His221Tyr	missense_variant	Exon 6 of 8	ENST00000353151.4	NP_001882.1
CSN2	NM_001302770.2	c.658C>T	p.His220Tyr	missense_variant	Exon 6 of 8		NP_001289699.1
CSN2	NM_001385731.1	c.616C>T	p.His206Tyr	missense_variant	Exon 5 of 7		NP_001372660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSN2	ENST00000353151.4	c.661C>T	p.His221Tyr	missense_variant	Exon 6 of 8	1	NM_001891.4	ENSP00000341030.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Aug 21, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.12
DANN	Benign	0.23
DEOGEN2	Benign	0.27	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0020	N
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.14	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.061
Sift	Benign	0.59	T
Sift4G	Benign	0.75	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.24		Loss of glycosylation at S225 (P = 0.025);
MVP		0.14
MPC		0.0021
ClinPred		0.035	T
GERP RS		-2.3
Varity_R		0.031
gMVP		0.094

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-70823006;