Genetic Variant CSN1S1:p.Asp166His (chr4-69944943-G-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001890.2(CSN1S1):c.496G>C(p.Asp166His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000432 in 1,612,650 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. D166N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0022 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 4 hom. )

Consequence

CSN1S1
NM_001890.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.274

Publications

5 publications found

Variant links:

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]

CSN1S1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057938397).

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSN1S1	NM_001890.2 link	c.496G>C	p.Asp166His	missense_variant	Exon 15 of 16	ENST00000246891.9	NP_001881.1	P47710-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSN1S1	ENST00000246891.9 link	c.496G>C	p.Asp166His	missense_variant	Exon 15 of 16	1	NM_001890.2	ENSP00000246891.4		P47710-1

Frequencies

GnomAD3 genomes

AF:

0.00217

AC:

330

AN:

151744

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00763

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000592

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:

0.00240

GnomAD2 exomes

AF:

0.000478

AC:

119

AN:

248816

AF XY:

0.000407

show subpopulations

Gnomad AFR exome

AF:

0.00731

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000251

AC:

366

AN:

1460790

Hom.:

Cov.:

AF XY:

0.000222

AC XY:

161

AN XY:

726714

show subpopulations

African (AFR)

AF:

0.00946

AC:

316

AN:

33398

American (AMR)

AF:

0.000224

AC:

AN:

44618

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.000521

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111310

Other (OTH)

AF:

0.000448

AC:

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00218

AC:

331

AN:

151860

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

148

AN XY:

74184

show subpopulations

African (AFR)

AF:

0.00763

AC:

316

AN:

41426

American (AMR)

AF:

0.000591

AC:

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5136

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10550

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67944

Other (OTH)

AF:

0.00237

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000113

Hom.:

Bravo

AF:

0.00237

ESP6500AA

AF:

0.00756

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000554

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000546

EpiControl

AF:

0.000178

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.36

T;.;.;T;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.65

T;T;T;T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.0058

T;T;T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.7

L;.;.;.;.

PhyloP100

-0.27

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-3.7

D;D;D;D;D

REVEL

Benign

0.053

Sift

Uncertain

0.0040

D;D;D;D;D

Sift4G

Uncertain

0.023

D;D;D;D;D

Polyphen

1.0

D;.;D;.;.

Vest4

0.33

MVP

0.40

MPC

0.27

ClinPred

0.12

GERP RS

-3.6

Varity_R

0.11

gMVP

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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4-69944943-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over