9-2029018-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003070.5(SMARCA2):c.-5G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0976 in 1,547,988 control chromosomes in the GnomAD database, including 8,722 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1599 hom., cov: 33)
  • Exomes 𝑓: 0.094 (7123 hom.)
• Consequence: SMARCA2 NM_003070.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.00500

Genes affected

SMARCA2 (HGNC:11098): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2) The protein encoded by this gene is a member of the SWI/SNF family of proteins and is highly similar to the brahma protein of Drosophila. 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 is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. Alternatively spliced transcript variants encoding different isoforms have been found for this gene, which contains a trinucleotide repeat (CAG) length polymorphism. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 9-2029018-G-A is Benign according to our data. Variant chr9-2029018-G-A is described in ClinVar as [Benign]. Clinvar id is 126341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA2	NM_003070.5	c.-5G>A		5_prime_UTR_variant	2/34	ENST00000349721.8
SMARCA2	NM_001289396.1	c.-5G>A		5_prime_UTR_variant	2/34
SMARCA2	NM_001289397.2	c.-5G>A		5_prime_UTR_variant	2/33
SMARCA2	NM_139045.4	c.-5G>A		5_prime_UTR_variant	2/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA2	ENST00000349721.8	c.-5G>A		5_prime_UTR_variant	2/34	5	NM_003070.5	P2

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19743 AN: 152192 Hom.: 1590 Cov.: 33

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.0807

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.0750

Gnomad FIN AF: 0.0578

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0842

Gnomad OTH AF: 0.110

GnomAD3 exomes AF: 0.115 AC: 17070 AN: 149066 Hom.: 1394 AF XY: 0.108 AC XY: 8586 AN XY: 79660

Gnomad AFR exome AF: 0.219

Gnomad AMR exome AF: 0.249

Gnomad ASJ exome AF: 0.0766

Gnomad EAS exome AF: 0.126

Gnomad SAS exome AF: 0.0704

Gnomad FIN exome AF: 0.0511

Gnomad NFE exome AF: 0.0833

Gnomad OTH exome AF: 0.0969

GnomAD4 exome AF: 0.0940 AC: 131232 AN: 1395678 Hom.: 7123 Cov.: 33 AF XY: 0.0922 AC XY: 63467 AN XY: 688540

Gnomad4 AFR exome AF: 0.219

Gnomad4 AMR exome AF: 0.244

Gnomad4 ASJ exome AF: 0.0783

Gnomad4 EAS exome AF: 0.141

Gnomad4 SAS exome AF: 0.0716

Gnomad4 FIN exome AF: 0.0522

Gnomad4 NFE exome AF: 0.0879

Gnomad4 OTH exome AF: 0.0970

GnomAD4 genome AF: 0.130 AC: 19787 AN: 152310 Hom.: 1599 Cov.: 33 AF XY: 0.129 AC XY: 9610 AN XY: 74470

Gnomad4 AFR AF: 0.216

Gnomad4 AMR AF: 0.195

Gnomad4 ASJ AF: 0.0807

Gnomad4 EAS AF: 0.114

Gnomad4 SAS AF: 0.0749

Gnomad4 FIN AF: 0.0578

Gnomad4 NFE AF: 0.0842

Gnomad4 OTH AF: 0.112

Alfa AF: 0.0999 Hom.: 815

Bravo AF: 0.148

Asia WGS AF: 0.116 AC: 403 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 15, 2013

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Nicolaides-Baraitser syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 03, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	9.6
Dann	Benign	0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs10964468; hg19: chr9-2029018; COSMIC: COSV100571671; COSMIC: COSV100571671;