rs2066518

Positions:

chr2-216423665-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_014140.4(SMARCAL1):c.1129G>C(p.Glu377Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0198 in 1,613,744 control chromosomes in the GnomAD database, including 1,175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.035 ( 208 hom., cov: 33)

Exomes 𝑓: 0.018 ( 967 hom. )

Consequence

SMARCAL1
NM_014140.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 5.67

Variant links:

Genes affected

SMARCAL1 (HGNC:11102): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a like 1) The protein encoded by this gene is a member of the SWI/SNF family of proteins. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein shows sequence similarity to the E. coli RNA polymerase-binding protein HepA. Mutations in this gene are a cause of Schimke immunoosseous dysplasia (SIOD), an autosomal recessive disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction, and T-cell immunodeficiency. [provided by RefSeq, Jul 2008]

SMARCAL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 2-216423665-G-C is Benign according to our data. Variant chr2-216423665-G-C is described in ClinVar as [Benign]. Clinvar id is 198202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-216423665-G-C is described in Lovd as [Benign]. Variant chr2-216423665-G-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCAL1	NM_014140.4 linkuse as main transcript	c.1129G>C	p.Glu377Gln	missense_variant	6/18	ENST00000357276.9	NP_054859.2
SMARCAL1	NM_001127207.2 linkuse as main transcript	c.1129G>C	p.Glu377Gln	missense_variant	6/18		NP_001120679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCAL1	ENST00000357276.9 linkuse as main transcript	c.1129G>C	p.Glu377Gln	missense_variant	6/18	2	NM_014140.4	ENSP00000349823	P1

Frequencies

GnomAD3 genomes

AF:

0.0351

AC:

5346

AN:

152152

Hom.:

210

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0745

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0130

Gnomad ASJ

AF:

0.0216

Gnomad EAS

AF:

0.158

Gnomad SAS

AF:

0.0684

Gnomad FIN

AF:

0.00829

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.00964

Gnomad OTH

AF:

0.0335

GnomAD3 exomes

AF:

0.0323

AC:

8121

AN:

251456

Hom.:

378

AF XY:

0.0324

AC XY:

4403

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.0738

Gnomad AMR exome

AF:

0.00942

Gnomad ASJ exome

AF:

0.0230

Gnomad EAS exome

AF:

0.157

Gnomad SAS exome

AF:

0.0633

Gnomad FIN exome

AF:

0.0111

Gnomad NFE exome

AF:

0.0102

Gnomad OTH exome

AF:

0.0236

GnomAD4 exome

AF:

0.0182

AC:

26634

AN:

1461474

Hom.:

967

Cov.:

AF XY:

0.0194

AC XY:

14134

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.0753

Gnomad4 AMR exome

AF:

0.00982

Gnomad4 ASJ exome

AF:

0.0229

Gnomad4 EAS exome

AF:

0.161

Gnomad4 SAS exome

AF:

0.0637

Gnomad4 FIN exome

AF:

0.0102

Gnomad4 NFE exome

AF:

0.00781

Gnomad4 OTH exome

AF:

0.0271

GnomAD4 genome

AF:

0.0351

AC:

5341

AN:

152270

Hom.:

208

Cov.:

AF XY:

0.0365

AC XY:

2721

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0744

Gnomad4 AMR

AF:

0.0129

Gnomad4 ASJ

AF:

0.0216

Gnomad4 EAS

AF:

0.158

Gnomad4 SAS

AF:

0.0678

Gnomad4 FIN

AF:

0.00829

Gnomad4 NFE

AF:

0.00966

Gnomad4 OTH

AF:

0.0331

Alfa

AF:

0.0175

Hom.:

Bravo

AF:

0.0371

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.0783

AC:

345

ESP6500EA

AF:

0.00907

AC:

ExAC

AF:

0.0333

AC:

4040

Asia WGS

AF:

0.104

AC:

362

AN:

3478

EpiCase

AF:

0.0110

EpiControl

AF:

0.0117

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Schimke immuno-osseous dysplasia

Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 21, 2014	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 27884173, 17089404, 25748404, 20981092) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Focal segmental glomerulosclerosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.021

T;T;T;T

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

.;D;D;T

MetaRNN

Benign

0.0017

T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.6

M;M;.;.

MutationTaster

Benign

0.000080

P;P

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.1

N;N;N;N

REVEL

Benign

0.25

Sift

Benign

0.068

T;T;T;D

Sift4G

Uncertain

0.041

D;D;T;D

Polyphen

0.42

B;B;.;.

Vest4

0.083

MPC

0.81

ClinPred

0.025

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.31

Position offset: 18

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