chr4-69939191-A-G

Variant names:

• chr4-69939191-A-G
• rs200177207
• NM_001890.2:c.259A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001890.2(CSN1S1):​c.259A>G​(p.Ile87Val) variant causes a missense change. The variant allele was found at a frequency of 0.000475 in 1,600,260 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: CSN1S1 NM_001890.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.67
• Publications: 4 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.034856915).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSN1S1	NM_001890.2	c.259A>G	p.Ile87Val	missense_variant	Exon 10 of 16	ENST00000246891.9	NP_001881.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSN1S1	ENST00000246891.9	c.259A>G	p.Ile87Val	missense_variant	Exon 10 of 16	1	NM_001890.2	ENSP00000246891.4

Frequencies

GnomAD3 genomes AF: 0.000369 AC: 56 AN: 151762 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

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: 0.000590

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000216 AC: 53 AN: 244886 AF XY: 0.000248

Gnomad AFR exome AF: 0.0000653

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: 0.000465

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000486 AC: 704 AN: 1448380 Hom.: 0 Cov.: 26 AF XY: 0.000511 AC XY: 368 AN XY: 720746

African (AFR) AF: 0.0000605 AC: 2 AN: 33042

American (AMR) AF: 0.00 AC: 0 AN: 43942

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25826

East Asian (EAS) AF: 0.00 AC: 0 AN: 39432

South Asian (SAS) AF: 0.00 AC: 0 AN: 84692

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.000605 AC: 667 AN: 1102612

Other (OTH) AF: 0.000568 AC: 34 AN: 59832

GnomAD4 genome AF: 0.000369 AC: 56 AN: 151880 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74250

African (AFR) AF: 0.000361 AC: 15 AN: 41546

American (AMR) AF: 0.00 AC: 0 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000590 AC: 40 AN: 67772

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000489 Hom.: 0

Bravo AF: 0.000325

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000861 AC: 7

ExAC AF: 0.000199 AC: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.259A>G (p.I87V) alteration is located in exon 10 (coding exon 9) of the CSN1S1 gene. This alteration results from a A to G substitution at nucleotide position 259, causing the isoleucine (I) at amino acid position 87 to be replaced by a valine (V). 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	0.080
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	8.0
DANN	Benign	0.20
DEOGEN2	Benign	0.045	T;.;.;T;.;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.40	T;T;T;T;T;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.035	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;.;.;.;.;.
PhyloP100		3.7
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.070	N;N;N;N;.;N
REVEL	Benign	0.17
Sift	Benign	1.0	T;T;T;T;.;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.23	B;.;B;.;.;.
Vest4		0.16
MVP		0.17
MPC		0.032
ClinPred		0.10	T
GERP RS		5.1
PromoterAI		0.0049	Neutral
Varity_R		0.059
gMVP		0.015

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs200177207; hg19: chr4-70804909;