9-2032845-G-T

Variant names:

• chr9-2032845-G-T
• rs1112534
• NM_003070.5:c.226-107G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003070.5(SMARCA2):​c.226-107G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000121 in 823,560 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: SMARCA2 NM_003070.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.372
• Publications: 0 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: PanelApp Australia, Orphanet, G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• blepharophimosis-impaired intellectual development syndrome

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003070.5. 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
	SMARCA2	NM_003070.5	MANE Select	c.226-107G>T		intron	N/A	NP_003061.3
	SMARCA2	NM_001289396.2		c.226-107G>T		intron	N/A	NP_001276325.1	P51531-1
	SMARCA2	NM_139045.4		c.226-107G>T		intron	N/A	NP_620614.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA2	ENST00000349721.8	TSL:5 MANE Select	c.226-107G>T		intron	N/A	ENSP00000265773.5	P51531-1
	SMARCA2	ENST00000382203.5	TSL:1	c.226-107G>T		intron	N/A	ENSP00000371638.1	P51531-1
	SMARCA2	ENST00000450198.6	TSL:1	c.226-107G>T		intron	N/A	ENSP00000392081.2	F6VDE0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000121 AC: 1 AN: 823560 Hom.: 0 AF XY: 0.00000237 AC XY: 1 AN XY: 421642

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 19466

American (AMR) AF: 0.00 AC: 0 AN: 25460

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16472

East Asian (EAS) AF: 0.00 AC: 0 AN: 34314

South Asian (SAS) AF: 0.00 AC: 0 AN: 55178

European-Finnish (FIN) AF: 0.0000233 AC: 1 AN: 42900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3650

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 587862

Other (OTH) AF: 0.00 AC: 0 AN: 38258

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.6
DANN	Benign	0.49
PhyloP100		0.37

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: rs1112534; hg19: chr9-2032845;