2-216450941-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_014140.4(SMARCAL1):c.1947C>T(p.Asp649Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0207 in 1,614,180 control chromosomes in the GnomAD database, including 470 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 34 hom., cov: 32)

Exomes 𝑓: 0.021 ( 436 hom. )

Consequence

SMARCAL1
NM_014140.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: -2.87

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

Schimke immuno-osseous dysplasia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

SMARCAL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 2-216450941-C-T is Benign according to our data. Variant chr2-216450941-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.87 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.018 (2739/152312) while in subpopulation SAS AF = 0.0263 (127/4826). AF 95% confidence interval is 0.0232. There are 34 homozygotes in GnomAd4. There are 1395 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCAL1	NM_014140.4 link	c.1947C>T	p.Asp649Asp	synonymous_variant	Exon 12 of 18	ENST00000357276.9	NP_054859.2	Q9NZC9
SMARCAL1	NM_001127207.2 link	c.1947C>T	p.Asp649Asp	synonymous_variant	Exon 12 of 18		NP_001120679.1	Q9NZC9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCAL1	ENST00000357276.9 link	c.1947C>T	p.Asp649Asp	synonymous_variant	Exon 12 of 18	2	NM_014140.4	ENSP00000349823.4		Q9NZC9

Frequencies

GnomAD3 genomes

AF:

0.0180

AC:

2740

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00282

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.0158

Gnomad ASJ

AF:

0.0640

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0263

Gnomad FIN

AF:

0.0288

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0242

Gnomad OTH

AF:

0.0220

GnomAD2 exomes

AF:

0.0231

AC:

5801

AN:

251308

AF XY:

0.0248

show subpopulations

Gnomad AFR exome

AF:

0.00308

Gnomad AMR exome

AF:

0.0124

Gnomad ASJ exome

AF:

0.0738

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0278

Gnomad NFE exome

AF:

0.0250

Gnomad OTH exome

AF:

0.0321

GnomAD4 exome

AF:

0.0210

AC:

30729

AN:

1461868

Hom.:

436

Cov.:

AF XY:

0.0218

AC XY:

15860

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.00248

AC:

AN:

33480

American (AMR)

AF:

0.0125

AC:

559

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0712

AC:

1860

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0311

AC:

2686

AN:

86258

European-Finnish (FIN)

AF:

0.0280

AC:

1496

AN:

53418

Middle Eastern (MID)

AF:

0.0444

AC:

256

AN:

5768

European-Non Finnish (NFE)

AF:

0.0201

AC:

22345

AN:

1111988

Other (OTH)

AF:

0.0239

AC:

1441

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

1853

3706

5559

7412

9265

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

752

1504

2256

3008

3760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0180

AC:

2739

AN:

152312

Hom.:

Cov.:

AF XY:

0.0187

AC XY:

1395

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00281

AC:

117

AN:

41572

American (AMR)

AF:

0.0157

AC:

241

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0640

AC:

222

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.0263

AC:

127

AN:

4826

European-Finnish (FIN)

AF:

0.0288

AC:

306

AN:

10610

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0242

AC:

1647

AN:

68026

Other (OTH)

AF:

0.0218

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

144

288

431

575

719

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0231

Hom.:

Bravo

AF:

0.0150

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0249

EpiControl

AF:

0.0235

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Schimke immuno-osseous dysplasia

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2Other:1

May 16, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Focal segmental glomerulosclerosis

Benign:1

Oct 27, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

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

-0.64

CADD

Benign

6.6

(source)

DANN

Benign

0.52

PhyloP100

-2.9

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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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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