4-69934693-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001890.2(CSN1S1):​c.88C>A​(p.Pro30Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000056 in 1,608,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P30S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CSN1S1 NM_001890.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.82
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09802374).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001890.2. 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
	CSN1S1	NM_001890.2	MANE Select	c.88C>A	p.Pro30Thr	missense	Exon 4 of 16	NP_001881.1	P47710-1
	CSN1S1	NM_001025104.2		c.88C>A	p.Pro30Thr	missense	Exon 4 of 15	NP_001020275.1	P47710-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSN1S1	ENST00000246891.9	TSL:1 MANE Select	c.88C>A	p.Pro30Thr	missense	Exon 4 of 16	ENSP00000246891.4	P47710-1
	CSN1S1	ENST00000949200.1		c.88C>A	p.Pro30Thr	missense	Exon 4 of 16	ENSP00000619259.1
	CSN1S1	ENST00000507772.5	TSL:5	c.88C>A	p.Pro30Thr	missense	Exon 3 of 14	ENSP00000427490.1	E9PDQ1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247578 AF XY: 0.00000744

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000481 AC: 7 AN: 1456434 Hom.: 0 Cov.: 29 AF XY: 0.00000690 AC XY: 5 AN XY: 724708

African (AFR) AF: 0.00 AC: 0 AN: 33272

American (AMR) AF: 0.00 AC: 0 AN: 44476

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.00 AC: 0 AN: 85950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53236

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

European-Non Finnish (NFE) AF: 0.00000632 AC: 7 AN: 1108002

Other (OTH) AF: 0.00 AC: 0 AN: 60150

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152100 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74290

African (AFR) AF: 0.0000241 AC: 1 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.000274 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	12
DANN	Benign	0.15
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.8
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.063
Sift	Benign	0.077	T
Sift4G	Benign	0.33	T
Polyphen		0.57	P
Vest4		0.092
MVP		0.34
MPC		0.064
ClinPred		0.065	T
GERP RS		3.1
Varity_R		0.034
gMVP		0.081

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs372882247; hg19: chr4-70800411;