Genetic Variant NM_001890.2:c.199A>G (chr4-69937124-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001890.2(CSN1S1):c.199A>G(p.Thr67Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000036 in 1,390,624 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: not found (cov: 30)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

CSN1S1
NM_001890.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.910

Publications

1 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: 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=0.0719271).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSN1S1	NM_001890.2 link	c.199A>G	p.Thr67Ala	missense_variant	Exon 8 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.199A>G	p.Thr67Ala	missense_variant	Exon 8 of 16	1	NM_001890.2	ENSP00000246891.4		P47710-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000258

AC:

AN:

155172

AF XY:

0.0000122

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000172

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000360

AC:

AN:

1390624

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

686018

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31004

American (AMR)

AF:

0.000146

AC:

AN:

34316

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24938

East Asian (EAS)

AF:

0.00

AC:

AN:

35656

South Asian (SAS)

AF:

0.00

AC:

AN:

77414

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49296

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5644

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1074710

Other (OTH)

AF:

0.00

AC:

AN:

57646

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.001398), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.385

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000937

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 11, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.199A>G (p.T67A) alteration is located in exon 8 (coding exon 7) of the CSN1S1 gene. This alteration results from a A to G substitution at nucleotide position 199, causing the threonine (T) at amino acid position 67 to be replaced by an alanine (A). 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

0.084

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.69

CADD

Benign

2.0

(source)

DANN

Benign

0.21

DEOGEN2

Benign

0.33

T;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.098

LIST_S2

Benign

0.33

T;T;T

M_CAP

Benign

0.0031

MetaRNN

Benign

0.072

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.4

L;.;.

PhyloP100

0.91

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.7

D;D;D

REVEL

Benign

0.019

Sift

Benign

0.31

T;T;T

Sift4G

Benign

0.53

T;T;T

Polyphen

0.018

B;.;B

Vest4

0.031

MutPred

0.22

Loss of phosphorylation at T67 (P = 0.013);.;Loss of phosphorylation at T67 (P = 0.013);

MVP

0.24

MPC

0.046

ClinPred

0.046

GERP RS

2.2

Varity_R

0.065

gMVP

0.057

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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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NM_001890.2:c.199A>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over