rs2186369

Variant names:

• chr22-23828809-T-G
• rs2186369
• NM_003073.5:c.986+3394T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003073.5(SMARCB1):​c.986+3394T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 152,130 control chromosomes in the GnomAD database, including 2,458 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.17 (2458 hom., cov: 32)
• Consequence: SMARCB1 NM_003073.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.540
• Publications: 15 publications found

Genes affected

SMARCB1 (HGNC:11103): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1) The protein encoded by this gene is part of a complex that relieves repressive chromatin structures, allowing the transcriptional machinery to access its targets more effectively. The encoded nuclear protein may also bind to and enhance the DNA joining activity of HIV-1 integrase. This gene has been found to be a tumor suppressor, and mutations in it have been associated with malignant rhabdoid tumors. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2015]

SMARCB1 Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• intellectual disability, autosomal dominant 15

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• rhabdoid tumor predisposition syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• SMARCB1-related schwannomatosis

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics
• familial multiple meningioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial rhabdoid tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• schwannomatosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003073.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCB1	NM_003073.5	MANE Select	c.986+3394T>G		intron	N/A	NP_003064.2
	SMARCB1	NM_001362877.2		c.1040+3394T>G		intron	N/A	NP_001349806.1
	SMARCB1	NM_001317946.2		c.1013+3394T>G		intron	N/A	NP_001304875.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCB1	ENST00000644036.2	MANE Select	c.986+3394T>G		intron	N/A	ENSP00000494049.2
	SMARCB1	ENST00000407422.8	TSL:1	c.959+3394T>G		intron	N/A	ENSP00000383984.3
	SMARCB1	ENST00000263121.12	TSL:1	c.848+3394T>G		intron	N/A	ENSP00000263121.8

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26177 AN: 152012 Hom.: 2459 Cov.: 32

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.0170

Gnomad SAS AF: 0.0375

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.154

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.172 AC: 26195 AN: 152130 Hom.: 2458 Cov.: 32 AF XY: 0.169 AC XY: 12536 AN XY: 74362

African (AFR) AF: 0.258 AC: 10689 AN: 41496

American (AMR) AF: 0.128 AC: 1959 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 484 AN: 3464

East Asian (EAS) AF: 0.0171 AC: 88 AN: 5160

South Asian (SAS) AF: 0.0379 AC: 183 AN: 4824

European-Finnish (FIN) AF: 0.160 AC: 1690 AN: 10570

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10612 AN: 68004

Other (OTH) AF: 0.153 AC: 323 AN: 2114

Alfa AF: 0.165 Hom.: 2925

Bravo AF: 0.176

Asia WGS AF: 0.0480 AC: 166 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.7
DANN	Benign	0.68
PhyloP100		-0.54
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: rs2186369; hg19: chr22-24170996;