2-216450941-C-T

Variant names:

• chr2-216450941-C-T
• rs2066526
• NM_014140.4:c.1947C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -2.87
• Publications: 3 publications found

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: ClinGen, PanelApp Australia, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014140.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCAL1	NM_014140.4	MANE Select	c.1947C>T	p.Asp649Asp	synonymous	Exon 12 of 18	NP_054859.2
	SMARCAL1	NM_001127207.2		c.1947C>T	p.Asp649Asp	synonymous	Exon 12 of 18	NP_001120679.1	Q9NZC9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCAL1	ENST00000357276.9	TSL:2 MANE Select	c.1947C>T	p.Asp649Asp	synonymous	Exon 12 of 18	ENSP00000349823.4	Q9NZC9
	SMARCAL1	ENST00000358207.9	TSL:1	c.1947C>T	p.Asp649Asp	synonymous	Exon 12 of 18	ENSP00000350940.5	Q9NZC9
	SMARCAL1	ENST00000392128.6	TSL:1	c.1473C>T	p.Asp491Asp	synonymous	Exon 9 of 15	ENSP00000375974.2	H7BYI2

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2740 AN: 152194 Hom.: 34 Cov.: 32

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

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.: 31 AF XY: 0.0218 AC XY: 15860 AN XY: 727234

African (AFR) AF: 0.00248 AC: 83 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: 3 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

GnomAD4 genome AF: 0.0180 AC: 2739 AN: 152312 Hom.: 34 Cov.: 32 AF XY: 0.0187 AC XY: 1395 AN XY: 74466

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: 2 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: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0242 AC: 1647 AN: 68026

Other (OTH) AF: 0.0218 AC: 46 AN: 2112

Alfa AF: 0.0231 Hom.: 29

Bravo AF: 0.0150

Asia WGS AF: 0.0120 AC: 41 AN: 3478

EpiCase AF: 0.0249

EpiControl AF: 0.0235

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Schimke immuno-osseous dysplasia (3)
-	-	2	not provided (3)
-	-	1	Focal segmental glomerulosclerosis (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	6.6
DANN	Benign	0.52
PhyloP100		-2.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2066526; hg19: chr2-217315664; COSMIC: COSV107417288; COSMIC: COSV107417288;