4-69957342-G-A

Variant names:

• chr4-69957342-G-A
• rs138138352
• NM_001891.4:c.607C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_001891.4(CSN2):​c.607C>T​(p.Leu203Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000277 in 1,453,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CSN2 NM_001891.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0750
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP7: Synonymous conserved (PhyloP=-0.075 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001891.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSN2	NM_001891.4	MANE Select	c.607C>T	p.Leu203Leu	synonymous	Exon 6 of 8	NP_001882.1	P05814
	CSN2	NM_001302770.2		c.604C>T	p.Leu202Leu	synonymous	Exon 6 of 8	NP_001289699.1
	CSN2	NM_001385731.1		c.562C>T	p.Leu188Leu	synonymous	Exon 5 of 7	NP_001372660.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSN2	ENST00000353151.4	TSL:1 MANE Select	c.607C>T	p.Leu203Leu	synonymous	Exon 6 of 8	ENSP00000341030.3	P05814

Frequencies

GnomAD3 genomes AF: 0.0000398 AC: 6 AN: 150828 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000490

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000405 AC: 10 AN: 247172 AF XY: 0.0000374

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000206

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.0000573

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000277 AC: 403 AN: 1453226 Hom.: 0 Cov.: 31 AF XY: 0.000287 AC XY: 207 AN XY: 722152

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000899 AC: 3 AN: 33368

American (AMR) AF: 0.000932 AC: 41 AN: 43990

Ashkenazi Jewish (ASJ) AF: 0.000155 AC: 4 AN: 25868

East Asian (EAS) AF: 0.00727 AC: 272 AN: 37418

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85752

European-Finnish (FIN) AF: 0.0000754 AC: 4 AN: 53082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.0000632 AC: 70 AN: 1107986

Other (OTH) AF: 0.000133 AC: 8 AN: 60022

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000397 AC: 6 AN: 150946 Hom.: 0 Cov.: 32 AF XY: 0.0000271 AC XY: 2 AN XY: 73762

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000489 AC: 2 AN: 40916

American (AMR) AF: 0.00 AC: 0 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.000198 AC: 1 AN: 5060

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.0000443 AC: 3 AN: 67688

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.54
DANN	Benign	0.44
PhyloP100		-0.075

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

Other links and lift over

dbSNP: rs138138352; hg19: chr4-70823060;