chr9-2110274-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_003070.5(SMARCA2):​c.3313C>T​(p.Arg1105Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1105H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

SMARCA2
NM_003070.5 missense

Scores

17
1
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 4.97
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 Pathogenic. Variant got 19 ACMG points.

PM1
In a domain Helicase C-terminal (size 162) in uniprot entity SMCA2_HUMAN there are 25 pathogenic changes around while only 0 benign (100%) in NM_003070.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr9-2110275-G-A is described in Lovd as [Pathogenic].
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). GenCC has associacion of gene with intellectual disability-sparse hair-brachydactyly syndrome, Coffin-Siris syndrome 1.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.986
PP5
Variant 9-2110274-C-T is Pathogenic according to our data. Variant chr9-2110274-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 68769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2110274-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SMARCA2NM_003070.5 linkuse as main transcriptc.3313C>T p.Arg1105Cys missense_variant 24/34 ENST00000349721.8 NP_003061.3
SMARCA2NM_001289396.1 linkuse as main transcriptc.3313C>T p.Arg1105Cys missense_variant 24/34 NP_001276325.1
SMARCA2NM_139045.4 linkuse as main transcriptc.3313C>T p.Arg1105Cys missense_variant 24/33 NP_620614.2
SMARCA2NM_001289397.2 linkuse as main transcriptc.3139C>T p.Arg1047Cys missense_variant 24/33 NP_001276326.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SMARCA2ENST00000349721.8 linkuse as main transcriptc.3313C>T p.Arg1105Cys missense_variant 24/345 NM_003070.5 ENSP00000265773 P2P51531-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2Other:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxOct 31, 2023Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25249037, 22366787, 35811451) -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2023SMARCA2: PS2, PM1, PM2, PS4:Moderate, PP2, PP3, PP4 -
not provided, no classification providedliterature onlyUniProtKB/Swiss-Prot-- -
Nicolaides-Baraitser syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteFeb 02, 2022Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants in the helicase conserved C-terminal domain (DECIPHER). (SP) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Four alternative amino acid changes have been observed at this position in at least nine unrelated individuals with SMARCA2-related conditions (Clinvar, LOVD, PMIDs: 28333917, 23929686, 22366787). (SP) 0803 - This variant has limited previous evidence of pathogenicity in two unrelated individuals. This variant has been observed in two individuals with SMARCA2-related conditions, including one de novo case (ClinVar, LOVD, PMID: 28333917). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.45
CADD
Pathogenic
31
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.94
.;.;D;.;D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.93
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
1.0
.;D;.;D;D
M_CAP
Pathogenic
0.68
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
5.1
H;.;H;H;H
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-7.4
D;.;D;D;D
REVEL
Pathogenic
0.87
Sift
Pathogenic
0.0
D;.;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D
Polyphen
1.0
D;.;D;D;D
Vest4
0.97
MutPred
0.87
Loss of disorder (P = 0.0188);.;Loss of disorder (P = 0.0188);Loss of disorder (P = 0.0188);Loss of disorder (P = 0.0188);
MVP
0.98
MPC
2.8
ClinPred
1.0
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.96
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs281875192; hg19: chr9-2110274; COSMIC: COSV61805239; COSMIC: COSV61805239; API