9-2028942-A-G

Variant names:

• chr9-2028942-A-G
• rs10964466
• NM_003070.5:c.-36-45A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003070.5(SMARCA2):​c.-36-45A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,438,398 control chromosomes in the GnomAD database, including 10,038 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1015 hom., cov: 33)
  • Exomes 𝑓: 0.11 (9023 hom.)
• Consequence: SMARCA2 NM_003070.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.409
• Publications: 2 publications found

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]

SMARCA2 Gene-Disease associations (from GenCC):

• intellectual disability-sparse hair-brachydactyly syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 9-2028942-A-G is Benign according to our data. Variant chr9-2028942-A-G is described in ClinVar as [Benign]. Clinvar id is 1251909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA2	NM_003070.5	c.-36-45A>G		intron_variant	Intron 1 of 33	ENST00000349721.8	NP_003061.3
SMARCA2	NM_001289396.2	c.-36-45A>G		intron_variant	Intron 1 of 33		NP_001276325.1
SMARCA2	NM_139045.4	c.-36-45A>G		intron_variant	Intron 1 of 32		NP_620614.2
SMARCA2	NM_001289397.2	c.-36-45A>G		intron_variant	Intron 1 of 32		NP_001276326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA2	ENST00000349721.8	c.-36-45A>G		intron_variant	Intron 1 of 33	5	NM_003070.5	ENSP00000265773.5

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16280 AN: 152234 Hom.: 1009 Cov.: 33

Gnomad AFR AF: 0.0784

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.0813

Gnomad EAS AF: 0.259

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.0994

GnomAD4 exome AF: 0.113 AC: 144766 AN: 1286044 Hom.: 9023 Cov.: 19 AF XY: 0.113 AC XY: 71898 AN XY: 638992

African (AFR) AF: 0.0788 AC: 2204 AN: 27978

American (AMR) AF: 0.111 AC: 3060 AN: 27580

Ashkenazi Jewish (ASJ) AF: 0.0804 AC: 1883 AN: 23416

East Asian (EAS) AF: 0.263 AC: 9257 AN: 35252

South Asian (SAS) AF: 0.133 AC: 9767 AN: 73520

European-Finnish (FIN) AF: 0.138 AC: 6580 AN: 47596

Middle Eastern (MID) AF: 0.0391 AC: 151 AN: 3866

European-Non Finnish (NFE) AF: 0.107 AC: 105934 AN: 992846

Other (OTH) AF: 0.110 AC: 5930 AN: 53990

GnomAD4 genome AF: 0.107 AC: 16302 AN: 152354 Hom.: 1015 Cov.: 33 AF XY: 0.109 AC XY: 8129 AN XY: 74498

African (AFR) AF: 0.0785 AC: 3266 AN: 41592

American (AMR) AF: 0.118 AC: 1805 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0813 AC: 282 AN: 3470

East Asian (EAS) AF: 0.259 AC: 1342 AN: 5188

South Asian (SAS) AF: 0.152 AC: 735 AN: 4828

European-Finnish (FIN) AF: 0.132 AC: 1405 AN: 10616

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7209 AN: 68036

Other (OTH) AF: 0.106 AC: 224 AN: 2116

Alfa AF: 0.0958 Hom.: 993

Bravo AF: 0.101

Asia WGS AF: 0.230 AC: 799 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 08, 2018

GeneDx

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	-0.56
CADD	Benign	18
DANN	Benign	0.81
PhyloP100		0.41
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: rs10964466; hg19: chr9-2028942;