chr2-216420396-C-T

Variant names:

• chr2-216420396-C-T
• rs2066513
• NM_014140.4:c.960C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014140.4(SMARCAL1):​c.960C>T​(p.Ala320Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00456 in 1,614,142 control chromosomes in the GnomAD database, including 298 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A320A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0081 (52 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (246 hom.)
• Consequence: SMARCAL1 NM_014140.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.173
• Publications: 4 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=-0.67).
• BP6: Variant 2-216420396-C-T is Benign according to our data. Variant chr2-216420396-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 197798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.173 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0612 is higher than 0.05.

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.960C>T	p.Ala320Ala	synonymous	Exon 5 of 18	NP_054859.2
	SMARCAL1	NM_001127207.2		c.960C>T	p.Ala320Ala	synonymous	Exon 5 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.960C>T	p.Ala320Ala	synonymous	Exon 5 of 18	ENSP00000349823.4	Q9NZC9
	SMARCAL1	ENST00000358207.9	TSL:1	c.960C>T	p.Ala320Ala	synonymous	Exon 5 of 18	ENSP00000350940.5	Q9NZC9
	SMARCAL1	ENST00000392128.6	TSL:1	c.552C>T	p.Ala184Ala	synonymous	Exon 3 of 15	ENSP00000375974.2	H7BYI2

Frequencies

GnomAD3 genomes AF: 0.00807 AC: 1228 AN: 152160 Hom.: 51 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0646

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0242

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0168 AC: 4223 AN: 251414 AF XY: 0.0132

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.0233

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000492

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.00419 AC: 6130 AN: 1461864 Hom.: 246 Cov.: 32 AF XY: 0.00377 AC XY: 2739 AN XY: 727238

African (AFR) AF: 0.000657 AC: 22 AN: 33480

American (AMR) AF: 0.0962 AC: 4302 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 35 AN: 26136

East Asian (EAS) AF: 0.0239 AC: 950 AN: 39700

South Asian (SAS) AF: 0.00288 AC: 248 AN: 86258

European-Finnish (FIN) AF: 0.000168 AC: 9 AN: 53418

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.000306 AC: 340 AN: 1111994

Other (OTH) AF: 0.00339 AC: 205 AN: 60394

GnomAD4 genome AF: 0.00807 AC: 1229 AN: 152278 Hom.: 52 Cov.: 32 AF XY: 0.00935 AC XY: 696 AN XY: 74456

African (AFR) AF: 0.000939 AC: 39 AN: 41548

American (AMR) AF: 0.0645 AC: 987 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.0247 AC: 128 AN: 5184

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4824

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68022

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.000849 Hom.: 1

Bravo AF: 0.0127

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Schimke immuno-osseous dysplasia (4)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Kidney disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.6
DANN	Benign	0.45
PhyloP100		0.17
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2066513; hg19: chr2-217285119; COSMIC: COSV100619787;