9-2029057-A-G

Position:

• chr9-2029057-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_003070.5(SMARCA2):​c.35A>G​(p.His12Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000925 in 1,404,970 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000093 (0 hom.)
• Consequence: SMARCA2 NM_003070.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.23

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 Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMARCA2. . Gene score misZ: 5.054 (greater than the threshold 3.09). Trascript score misZ: 4.663 (greater than threshold 3.09). The gene has 93 curated pathogenic missense variants (we use a threshold of 10). The gene has 88 curated benign missense variants. GenCC has associacion of the gene with intellectual disability-sparse hair-brachydactyly syndrome, Coffin-Siris syndrome 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19824684).
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA2	NM_003070.5	c.35A>G	p.His12Arg	missense_variant	2/34	ENST00000349721.8	NP_003061.3
SMARCA2	NM_001289396.2	c.35A>G	p.His12Arg	missense_variant	2/34		NP_001276325.1
SMARCA2	NM_139045.4	c.35A>G	p.His12Arg	missense_variant	2/33		NP_620614.2
SMARCA2	NM_001289397.2	c.35A>G	p.His12Arg	missense_variant	2/33		NP_001276326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA2	ENST00000349721.8	c.35A>G	p.His12Arg	missense_variant	2/34	5	NM_003070.5	ENSP00000265773.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000612 AC: 1 AN: 163460 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 87376

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000219

GnomAD4 exome AF: 0.00000925 AC: 13 AN: 1404970 Hom.: 0 Cov.: 32 AF XY: 0.00000721 AC XY: 5 AN XY: 693850

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000111

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 23, 2024

The c.35A>G (p.H12R) alteration is located in exon 2 (coding exon 1) of the SMARCA2 gene. This alteration results from a A to G substitution at nucleotide position 35, causing the histidine (H) at amino acid position 12 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0060	.;.;T;T;T;T;T;.;T;T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.88	.;D;.;.;.;D;D;D;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.2	L;.;.;L;.;.;.;L;.;.;L
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.70	N;N;.;N;.;.;D;N;N;.;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.018	D;D;.;D;.;.;D;D;D;.;D
Sift4G	Benign	1.0	T;T;.;T;.;.;T;T;T;.;T
Polyphen		0.0010	B;.;.;B;.;.;.;B;.;.;B
Vest4		0.18
MutPred		0.22		Loss of glycosylation at P17 (P = 0.1769);Loss of glycosylation at P17 (P = 0.1769);Loss of glycosylation at P17 (P = 0.1769);Loss of glycosylation at P17 (P = 0.1769);Loss of glycosylation at P17 (P = 0.1769);Loss of glycosylation at P17 (P = 0.1769);Loss of glycosylation at P17 (P = 0.1769);Loss of glycosylation at P17 (P = 0.1769);Loss of glycosylation at P17 (P = 0.1769);Loss of glycosylation at P17 (P = 0.1769);Loss of glycosylation at P17 (P = 0.1769);
MVP		0.69
MPC		0.054
ClinPred		0.25	T
GERP RS		5.5
Varity_R		0.26
gMVP		0.042

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: rs1450657913; hg19: chr9-2029057;