chr9-2029072-C-A

Variant names:

• chr9-2029072-C-A
• rs543241889
• NM_003070.5:c.50C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_003070.5(SMARCA2):​c.50C>A​(p.Pro17Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000141 in 1,415,106 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMARCA2 NM_003070.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.17

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SMARCA2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 93 curated pathogenic missense variants (we use a threshold of 10). The gene has 88 curated benign missense variants. Gene score misZ: 5.054 (above the threshold of 3.09). Trascript score misZ: 4.663 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability-sparse hair-brachydactyly syndrome, Coffin-Siris syndrome 1.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA2	NM_003070.5	c.50C>A	p.Pro17Gln	missense_variant	Exon 2 of 34	ENST00000349721.8	NP_003061.3
SMARCA2	NM_001289396.2	c.50C>A	p.Pro17Gln	missense_variant	Exon 2 of 34		NP_001276325.1
SMARCA2	NM_139045.4	c.50C>A	p.Pro17Gln	missense_variant	Exon 2 of 33		NP_620614.2
SMARCA2	NM_001289397.2	c.50C>A	p.Pro17Gln	missense_variant	Exon 2 of 33		NP_001276326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA2	ENST00000349721.8	c.50C>A	p.Pro17Gln	missense_variant	Exon 2 of 34	5	NM_003070.5	ENSP00000265773.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1415106 Hom.: 0 Cov.: 32 AF XY: 0.00000143 AC XY: 1 AN XY: 699872

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: 0.00000184

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	.;.;T;T;T;T;T;.;T;T;T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	.;D;.;.;.;D;D;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.50	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	1.8	L;.;.;L;.;.;.;L;.;.;L
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.3	N;D;.;N;.;.;D;N;D;.;N
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D;D;.;D;.;.;D;D;D;.;D
Sift4G	Uncertain	0.047	D;D;.;D;.;.;D;D;D;.;D
Polyphen		1.0	D;.;.;D;.;.;.;D;.;.;D
Vest4		0.55
MutPred		0.18		Loss of glycosylation at P17 (P = 0.0309);Loss of glycosylation at P17 (P = 0.0309);Loss of glycosylation at P17 (P = 0.0309);Loss of glycosylation at P17 (P = 0.0309);Loss of glycosylation at P17 (P = 0.0309);Loss of glycosylation at P17 (P = 0.0309);Loss of glycosylation at P17 (P = 0.0309);Loss of glycosylation at P17 (P = 0.0309);Loss of glycosylation at P17 (P = 0.0309);Loss of glycosylation at P17 (P = 0.0309);Loss of glycosylation at P17 (P = 0.0309);
MVP		0.79
MPC		0.045
ClinPred		0.91	D
GERP RS		5.4
Varity_R		0.38
gMVP		0.26

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: rs543241889; hg19: chr9-2029072;