4-69934693-C-T

Variant names:

• chr4-69934693-C-T
• rs372882247
• NM_001890.2:c.88C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001890.2(CSN1S1):​c.88C>T​(p.Pro30Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000687 in 1,456,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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: 0.0000069 (0 hom.)
• Consequence: CSN1S1 NM_001890.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.82

Genes affected

CSN1S1 (HGNC:2445): (casein alpha s1) Predicted to be involved in response to dehydroepiandrosterone; response to estradiol; and response to steroid hormone. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08579013).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSN1S1	NM_001890.2	c.88C>T	p.Pro30Ser	missense_variant	Exon 4 of 16	ENST00000246891.9	NP_001881.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSN1S1	ENST00000246891.9	c.88C>T	p.Pro30Ser	missense_variant	Exon 4 of 16	1	NM_001890.2	ENSP00000246891.4
CSN1S1	ENST00000507772.5	c.88C>T	p.Pro30Ser	missense_variant	Exon 3 of 14	5		ENSP00000427490.1
CSN1S1	ENST00000507763.5	c.88C>T	p.Pro30Ser	missense_variant	Exon 3 of 14	5		ENSP00000422611.1
CSN1S1	ENST00000505782.5	c.88C>T	p.Pro30Ser	missense_variant	Exon 3 of 13	5		ENSP00000426684.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000687 AC: 10 AN: 1456434 Hom.: 0 Cov.: 29 AF XY: 0.00000552 AC XY: 4 AN XY: 724708

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: 0.00000903

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.88C>T (p.P30S) alteration is located in exon 4 (coding exon 3) of the CSN1S1 gene. This alteration results from a C to T substitution at nucleotide position 88, causing the proline (P) at amino acid position 30 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	0.096
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	11
DANN	Benign	0.20
DEOGEN2	Benign	0.037	T;.;.;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.54	T;T;T;T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.086	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.27	N;N;N;N
REVEL	Benign	0.030
Sift	Benign	0.11	T;T;T;T
Sift4G	Benign	0.42	T;T;T;T
Polyphen		0.40	B;.;B;.
Vest4		0.096
MutPred		0.19		Gain of phosphorylation at P30 (P = 0.0154);Gain of phosphorylation at P30 (P = 0.0154);Gain of phosphorylation at P30 (P = 0.0154);Gain of phosphorylation at P30 (P = 0.0154);
MVP		0.29
MPC		0.053
ClinPred		0.094	T
GERP RS		3.1
Varity_R		0.024
gMVP		0.077

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs372882247; hg19: chr4-70800411;