Genetic Variant CSN1S1:c.84+5A>G (chr4-69934249-A-G) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001890.2(CSN1S1):c.84+5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000602 in 1,610,634 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 8 hom. )

Consequence

CSN1S1
NM_001890.2 splice_region, intron

Scores

Splicing: ADA: 0.00002064

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.23

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 made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 4-69934249-A-G is Benign according to our data. Variant chr4-69934249-A-G is described in ClinVar as [Benign]. Clinvar id is 782694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSN1S1	NM_001890.2 link	c.84+5A>G		splice_region_variant, intron_variant	Intron 3 of 15	ENST00000246891.9	NP_001881.1	P47710-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CSN1S1	ENST00000246891.9 link	c.84+5A>G	splice_region_variant, intron_variant	Intron 3 of 15	1	NM_001890.2	ENSP00000246891.4	P47710-1
CSN1S1	ENST00000507772.5 link	c.84+5A>G	splice_region_variant, intron_variant	Intron 2 of 13	5		ENSP00000427490.1	E9PDQ1
CSN1S1	ENST00000507763.5 link	c.84+5A>G	splice_region_variant, intron_variant	Intron 2 of 13	5		ENSP00000422611.1	P47710-4
CSN1S1	ENST00000505782.5 link	c.84+5A>G	splice_region_variant, intron_variant	Intron 2 of 12	5		ENSP00000426684.1	D6RF34

Frequencies

GnomAD3 genomes

AF:

0.00176

AC:

268

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0167

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:

0.0000294

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00191

AC:

472

AN:

247506

Hom.:

AF XY:

0.00153

AC XY:

205

AN XY:

134338

show subpopulations

Gnomad AFR exome

AF:

0.000260

Gnomad AMR exome

AF:

0.0135

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000890

Gnomad OTH exome

AF:

0.00167

GnomAD4 exome

AF:

0.000481

AC:

701

AN:

1458464

Hom.:

Cov.:

AF XY:

0.000411

AC XY:

298

AN XY:

725636

show subpopulations

Gnomad4 AFR exome

AF:

0.000180

Gnomad4 AMR exome

AF:

0.0149

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000541

Gnomad4 OTH exome

AF:

0.000482

GnomAD4 genome

AF:

0.00176

AC:

268

AN:

152170

Hom.:

Cov.:

AF XY:

0.00235

AC XY:

175

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.0167

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000209

Hom.:

Bravo

AF:

0.00272

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 31, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Benign

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000021

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over