9-2123639-T-C

Variant names:

• chr9-2123639-T-C
• rs3829070
• NM_003070.5:c.3763-80T>C

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.3763-80T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 1,244,436 control chromosomes in the GnomAD database, including 26,125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (6317 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19808 hom.)
• Consequence: SMARCA2 NM_003070.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.831
• Publications: 5 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=-0.82).
• BP6: Variant 9-2123639-T-C is Benign according to our data. Variant chr9-2123639-T-C is described in ClinVar as Benign. ClinVar VariationId is 1259756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.529 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA2	NM_003070.5	c.3763-80T>C		intron_variant	Intron 26 of 33	ENST00000349721.8	NP_003061.3
SMARCA2	NM_001289396.2	c.3763-80T>C		intron_variant	Intron 26 of 33		NP_001276325.1
SMARCA2	NM_139045.4	c.3763-80T>C		intron_variant	Intron 26 of 32		NP_620614.2
SMARCA2	NM_001289397.2	c.3589-80T>C		intron_variant	Intron 26 of 32		NP_001276326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA2	ENST00000349721.8	c.3763-80T>C		intron_variant	Intron 26 of 33	5	NM_003070.5	ENSP00000265773.5

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36771 AN: 151816 Hom.: 6293 Cov.: 32

Gnomad AFR AF: 0.457

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.547

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.212

GnomAD4 exome AF: 0.157 AC: 171064 AN: 1092502 Hom.: 19808 AF XY: 0.158 AC XY: 87595 AN XY: 555860

African (AFR) AF: 0.464 AC: 12445 AN: 26832

American (AMR) AF: 0.258 AC: 9804 AN: 37972

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 2547 AN: 23354

East Asian (EAS) AF: 0.580 AC: 21331 AN: 36784

South Asian (SAS) AF: 0.232 AC: 17309 AN: 74746

European-Finnish (FIN) AF: 0.175 AC: 8692 AN: 49782

Middle Eastern (MID) AF: 0.183 AC: 916 AN: 5008

European-Non Finnish (NFE) AF: 0.114 AC: 89758 AN: 789850

Other (OTH) AF: 0.172 AC: 8262 AN: 48174

GnomAD4 genome AF: 0.242 AC: 36842 AN: 151934 Hom.: 6317 Cov.: 32 AF XY: 0.247 AC XY: 18317 AN XY: 74258

African (AFR) AF: 0.458 AC: 18963 AN: 41406

American (AMR) AF: 0.198 AC: 3024 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 368 AN: 3466

East Asian (EAS) AF: 0.546 AC: 2814 AN: 5152

South Asian (SAS) AF: 0.249 AC: 1197 AN: 4810

European-Finnish (FIN) AF: 0.167 AC: 1763 AN: 10548

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.120 AC: 8177 AN: 67960

Other (OTH) AF: 0.211 AC: 445 AN: 2106

Alfa AF: 0.158 Hom.: 4485

Bravo AF: 0.256

Asia WGS AF: 0.375 AC: 1306 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	-0.82
CADD	Benign	0.11
DANN	Benign	0.66
PhyloP100		-0.83
PromoterAI		0.036	Neutral
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: rs3829070; hg19: chr9-2123639; COSMIC: COSV61806288; COSMIC: COSV61806288;