chr4-69944943-G-T

Variant names:

• chr4-69944943-G-T
• rs149927680
• NM_001890.2:c.496G>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001890.2(CSN1S1):​c.496G>T​(p.Asp166Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,612,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D166N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: CSN1S1 NM_001890.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.274
• Publications: 5 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 -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.34001577).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSN1S1	NM_001890.2	c.496G>T	p.Asp166Tyr	missense_variant	Exon 15 of 16	ENST00000246891.9	NP_001881.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSN1S1	ENST00000246891.9	c.496G>T	p.Asp166Tyr	missense_variant	Exon 15 of 16	1	NM_001890.2	ENSP00000246891.4

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151744 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000402 AC: 10 AN: 248816 AF XY: 0.0000370

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: 0.0000443

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000445 AC: 65 AN: 1460788 Hom.: 0 Cov.: 31 AF XY: 0.0000468 AC XY: 34 AN XY: 726712

African (AFR) AF: 0.000150 AC: 5 AN: 33398

American (AMR) AF: 0.00 AC: 0 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5758

European-Non Finnish (NFE) AF: 0.0000369 AC: 41 AN: 1111308

Other (OTH) AF: 0.0000663 AC: 4 AN: 60304

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151744 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74058

African (AFR) AF: 0.00 AC: 0 AN: 41306

American (AMR) AF: 0.0000658 AC: 1 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67952

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000113 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000497 AC: 6

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.496G>T (p.D166Y) alteration is located in exon 15 (coding exon 14) of the CSN1S1 gene. This alteration results from a G to T substitution at nucleotide position 496, causing the aspartic acid (D) at amino acid position 166 to be replaced by a tyrosine (Y). 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	0.19
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Uncertain	0.43	T;.;.;T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.57	T;T;T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.34	T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.7	L;.;.;.;.
PhyloP100		-0.27
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-5.4	D;D;D;D;D
REVEL	Benign	0.11
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D;D
Polyphen		1.0	D;.;D;.;.
Vest4		0.48
MutPred		0.57		Loss of disorder (P = 0.0245);.;.;.;.;
MVP		0.43
MPC		0.27
ClinPred		0.95	D
GERP RS		-3.6
Varity_R		0.11
gMVP		0.20

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

Other links and lift over

dbSNP: rs149927680; hg19: chr4-70810661;