Genetic Variant SS18L1:c.146+62C>A (chr20-62158810-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_198935.3(SS18L1):c.146+62C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0169 in 1,612,460 control chromosomes in the GnomAD database, including 2,561 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.075 ( 1320 hom., cov: 32)

Exomes 𝑓: 0.011 ( 1241 hom. )

Consequence

SS18L1
NM_198935.3 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.719

Publications

2 publications found

Variant links:

Genes affected

SS18L1 (HGNC:15592): (SS18L1 subunit of BAF chromatin remodeling complex) This gene encodes a calcium-responsive transactivator which is an essential subunit of a neuron-specific chromatin-remodeling complex. The structure of this gene is similar to that of the SS18 gene. Mutations in this gene are involved in amyotrophic lateral sclerosis (ALS). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2014]

SS18L1 Gene-Disease associations (from GenCC):

amyotrophic lateral sclerosis
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, ClinGen

SS18L1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005101472).

BP6

Variant 20-62158810-C-A is Benign according to our data. Variant chr20-62158810-C-A is described in ClinVar as [Benign]. Clinvar id is 1277479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SS18L1	NM_198935.3 link	c.146+62C>A		intron_variant	Intron 2 of 10	ENST00000331758.8	NP_945173.1	O75177-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SS18L1	ENST00000331758.8 link	c.146+62C>A		intron_variant	Intron 2 of 10	1	NM_198935.3	ENSP00000333012.3		O75177-1
SS18L1	ENST00000450482.5 link	c.23C>A	p.Ala8Asp	missense_variant	Exon 3 of 5	5		ENSP00000398634.1		Q9BR54

Frequencies

GnomAD3 genomes

AF:

0.0746

AC:

11345

AN:

152136

Hom.:

1314

Cov.:

show subpopulations

Gnomad AFR

AF:

0.251

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0327

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00444

Gnomad OTH

AF:

0.0483

GnomAD2 exomes

AF:

0.0224

AC:

5610

AN:

250502

AF XY:

0.0170

show subpopulations

Gnomad AFR exome

AF:

0.262

Gnomad AMR exome

AF:

0.0159

Gnomad ASJ exome

AF:

0.0152

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00130

Gnomad NFE exome

AF:

0.00450

Gnomad OTH exome

AF:

0.0155

GnomAD4 exome

AF:

0.0109

AC:

15891

AN:

1460206

Hom.:

1241

Cov.:

AF XY:

0.00981

AC XY:

7128

AN XY:

726384

show subpopulations

African (AFR)

AF:

0.261

AC:

8747

AN:

33472

American (AMR)

AF:

0.0171

AC:

766

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0147

AC:

385

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000870

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00136

AC:

AN:

52180

Middle Eastern (MID)

AF:

0.0271

AC:

156

AN:

5766

European-Non Finnish (NFE)

AF:

0.00390

AC:

4334

AN:

1111694

Other (OTH)

AF:

0.0225

AC:

1357

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

912

1823

2735

3646

4558

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0748

AC:

11384

AN:

152254

Hom.:

1320

Cov.:

AF XY:

0.0730

AC XY:

5438

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.251

AC:

10412

AN:

41498

American (AMR)

AF:

0.0326

AC:

499

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0130

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00145

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00444

AC:

302

AN:

68034

Other (OTH)

AF:

0.0478

AC:

101

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

434

869

1303

1738

2172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0612

Hom.:

794

Bravo

AF:

0.0849

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.244

AC:

765

ESP6500EA

AF:

0.00433

AC:

ExAC

AF:

0.0266

AC:

3232

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.00583

EpiControl

AF:

0.00569

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

- -

May 15, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.23

CADD

Benign

2.1

(source)

DANN

Benign

0.97

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.24

MetaRNN

Benign

0.0051

MetaSVM

Benign

-1.0

PhyloP100

-0.72

PROVEAN

Benign

-2.0

REVEL

Benign

0.035

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.016

ClinPred

0.040

GERP RS

1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

Publications

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20-62158810-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over