chr9-2029048-C-T

Variant names:

• chr9-2029048-C-T
• rs773325366
• NM_003070.5:c.26C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_003070.5(SMARCA2):​c.26C>T​(p.Ala9Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000148 in 1,553,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A9A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: SMARCA2 NM_003070.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 3.61
• Publications: 4 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17684153).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000143 (20/1401262) while in subpopulation MID AF = 0.0002 (1/4994). AF 95% confidence interval is 0.0000671. There are 0 homozygotes in GnomAdExome4. There are 14 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 20 AD gene.

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.26C>T	p.Ala9Val	missense	Exon 2 of 34	NP_003061.3
	SMARCA2	NM_001289396.2		c.26C>T	p.Ala9Val	missense	Exon 2 of 34	NP_001276325.1	P51531-1
	SMARCA2	NM_139045.4		c.26C>T	p.Ala9Val	missense	Exon 2 of 33	NP_620614.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA2	ENST00000349721.8	TSL:5 MANE Select	c.26C>T	p.Ala9Val	missense	Exon 2 of 34	ENSP00000265773.5	P51531-1
	SMARCA2	ENST00000382203.5	TSL:1	c.26C>T	p.Ala9Val	missense	Exon 2 of 34	ENSP00000371638.1	P51531-1
	SMARCA2	ENST00000450198.6	TSL:1	c.26C>T	p.Ala9Val	missense	Exon 2 of 33	ENSP00000392081.2	F6VDE0

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152264 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000317 AC: 5 AN: 157640 AF XY: 0.0000238

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000402

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000143 AC: 20 AN: 1401262 Hom.: 0 Cov.: 32 AF XY: 0.0000202 AC XY: 14 AN XY: 691702

African (AFR) AF: 0.00 AC: 0 AN: 31646

American (AMR) AF: 0.0000278 AC: 1 AN: 35960

Ashkenazi Jewish (ASJ) AF: 0.0000397 AC: 1 AN: 25204

East Asian (EAS) AF: 0.00 AC: 0 AN: 35938

South Asian (SAS) AF: 0.000125 AC: 10 AN: 79846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49274

Middle Eastern (MID) AF: 0.000200 AC: 1 AN: 4994

European-Non Finnish (NFE) AF: 0.00000648 AC: 7 AN: 1080370

Other (OTH) AF: 0.00 AC: 0 AN: 58030

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152264 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74394

African (AFR) AF: 0.00 AC: 0 AN: 41474

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000175 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Nicolaides-Baraitser syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	T
Eigen	Benign	0.014
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.6
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.25
Sift	Benign	0.086	T
Sift4G	Benign	0.21	T
Polyphen		0.30	B
Vest4		0.11
MVP		0.47
MPC		0.047
ClinPred		0.072	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.077
Mutation Taster		=75/25	polymorphism

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: rs773325366; hg19: chr9-2029048; COSMIC: COSV61810542; COSMIC: COSV61810542;