9-2029108-C-T

Variant names:

• chr9-2029108-C-T
• rs1412585591
• NM_003070.5:c.86C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM2 PP2 PP3 BS2

The NM_003070.5(SMARCA2):​c.86C>T​(p.Pro29Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,445,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: SMARCA2 NM_003070.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.90

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 0 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA2	NM_003070.5	c.86C>T	p.Pro29Leu	missense_variant	Exon 2 of 34	ENST00000349721.8	NP_003061.3
SMARCA2	NM_001289396.2	c.86C>T	p.Pro29Leu	missense_variant	Exon 2 of 34		NP_001276325.1
SMARCA2	NM_139045.4	c.86C>T	p.Pro29Leu	missense_variant	Exon 2 of 33		NP_620614.2
SMARCA2	NM_001289397.2	c.86C>T	p.Pro29Leu	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.86C>T	p.Pro29Leu	missense_variant	Exon 2 of 34	5	NM_003070.5	ENSP00000265773.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000889 AC: 2 AN: 224878 Hom.: 0 AF XY: 0.0000165 AC XY: 2 AN XY: 121564

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: 0.0000202

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1445740 Hom.: 0 Cov.: 33 AF XY: 0.00000557 AC XY: 4 AN XY: 717708

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: 0.00000453

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 07, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SMARCA2 c.86C>T (p.Pro29Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.9e-06 in 224878 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.86C>T in individuals affected with SMARCA2-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	.;.;T;T;T;T;T;.;T;T;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	.;D;.;.;.;D;D;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Benign	1.8	L;.;.;L;.;.;.;L;.;.;L
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.3	N;D;.;N;.;.;D;N;D;.;N
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D;D;.;D;.;.;D;D;D;.;D
Sift4G	Uncertain	0.0050	D;D;.;D;.;.;D;D;D;.;D
Polyphen		1.0	D;.;.;D;.;.;.;D;.;.;D
Vest4		0.65
MutPred		0.26		Gain of catalytic residue at P29 (P = 0.0127);Gain of catalytic residue at P29 (P = 0.0127);Gain of catalytic residue at P29 (P = 0.0127);Gain of catalytic residue at P29 (P = 0.0127);Gain of catalytic residue at P29 (P = 0.0127);Gain of catalytic residue at P29 (P = 0.0127);Gain of catalytic residue at P29 (P = 0.0127);Gain of catalytic residue at P29 (P = 0.0127);Gain of catalytic residue at P29 (P = 0.0127);Gain of catalytic residue at P29 (P = 0.0127);Gain of catalytic residue at P29 (P = 0.0127);
MVP		0.78
MPC		0.048
ClinPred		0.75	D
GERP RS		5.8
Varity_R		0.31
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1412585591; hg19: chr9-2029108;