9-2029084-C-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_003070.5(SMARCA2):​c.62C>A​(p.Pro21His) variant causes a missense change. The variant allele was found at a frequency of 0.00000421 in 1,426,524 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: 0.0000042 ( 0 hom. )

Consequence

SMARCA2
NM_003070.5 missense

Scores

1
8
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.98
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

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.
BP4
Computational evidence support a benign effect (MetaRNN=0.25757).
BS2
High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMARCA2NM_003070.5 linkc.62C>A p.Pro21His missense_variant Exon 2 of 34 ENST00000349721.8 NP_003061.3 P51531-1Q8N9Q1Q56A76
SMARCA2NM_001289396.2 linkc.62C>A p.Pro21His missense_variant Exon 2 of 34 NP_001276325.1 P51531-1Q8N9Q1B4DSC8
SMARCA2NM_139045.4 linkc.62C>A p.Pro21His missense_variant Exon 2 of 33 NP_620614.2 P51531-2Q8N9Q1Q56A76
SMARCA2NM_001289397.2 linkc.62C>A p.Pro21His missense_variant Exon 2 of 33 NP_001276326.1 P51531F6VDE0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SMARCA2ENST00000349721.8 linkc.62C>A p.Pro21His missense_variant Exon 2 of 34 5 NM_003070.5 ENSP00000265773.5 P51531-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000512
AC:
1
AN:
195458
Hom.:
0
AF XY:
0.00000949
AC XY:
1
AN XY:
105372
show subpopulations
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:
0.0000122
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000421
AC:
6
AN:
1426524
Hom.:
0
Cov.:
32
AF XY:
0.00000566
AC XY:
4
AN XY:
706644
show subpopulations
Gnomad4 AFR exome
AF:
0.0000308
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:
0.00000366
Gnomad4 OTH exome
AF:
0.0000170
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.000111
Hom.:
0
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.00000827
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jan 01, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.62C>A (p.P21H) alteration is located in exon 2 (coding exon 1) of the SMARCA2 gene. This alteration results from a C to A substitution at nucleotide position 62, causing the proline (P) at amino acid position 21 to be replaced by a histidine (H). 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
0.24
BayesDel_addAF
Uncertain
0.10
D
BayesDel_noAF
Benign
-0.090
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.077
.;.;T;D;T;T;T;.;T;T;D
Eigen
Benign
-0.0059
Eigen_PC
Benign
0.083
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.93
.;D;.;.;.;D;D;D;D;D;D
M_CAP
Uncertain
0.10
D
MetaRNN
Benign
0.26
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.41
D
MutationAssessor
Benign
1.7
L;.;.;L;.;.;.;L;.;.;L
PrimateAI
Pathogenic
0.82
D
PROVEAN
Benign
-2.2
N;D;.;N;.;.;D;N;D;.;N
REVEL
Uncertain
0.42
Sift
Uncertain
0.0040
D;D;.;D;.;.;D;D;D;.;D
Sift4G
Benign
0.068
T;T;.;T;.;.;D;T;D;.;T
Polyphen
0.51
P;.;.;B;.;.;.;P;.;.;B
Vest4
0.42
MutPred
0.20
Loss of glycosylation at P21 (P = 0.0323);Loss of glycosylation at P21 (P = 0.0323);Loss of glycosylation at P21 (P = 0.0323);Loss of glycosylation at P21 (P = 0.0323);Loss of glycosylation at P21 (P = 0.0323);Loss of glycosylation at P21 (P = 0.0323);Loss of glycosylation at P21 (P = 0.0323);Loss of glycosylation at P21 (P = 0.0323);Loss of glycosylation at P21 (P = 0.0323);Loss of glycosylation at P21 (P = 0.0323);Loss of glycosylation at P21 (P = 0.0323);
MVP
0.59
MPC
0.052
ClinPred
0.51
D
GERP RS
4.6
Varity_R
0.28
gMVP
0.22

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs776972919; hg19: chr9-2029084; API