dbSNP rs543241889: SMARCA2:p.Pro17Gln (chr9-2029072-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P17L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SMARCA2
NM_003070.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.17

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]

SMARCA2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA2	NM_003070.5 link	c.50C>A	p.Pro17Gln	missense_variant	Exon 2 of 34	ENST00000349721.8	NP_003061.3	P51531-1Q8N9Q1Q56A76
SMARCA2	NM_001289396.2 link	c.50C>A	p.Pro17Gln	missense_variant	Exon 2 of 34		NP_001276325.1	P51531-1Q8N9Q1B4DSC8
SMARCA2	NM_139045.4 link	c.50C>A	p.Pro17Gln	missense_variant	Exon 2 of 33		NP_620614.2	P51531-2Q8N9Q1Q56A76
SMARCA2	NM_001289397.2 link	c.50C>A	p.Pro17Gln	missense_variant	Exon 2 of 33		NP_001276326.1	P51531F6VDE0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA2	ENST00000349721.8 link	c.50C>A	p.Pro17Gln	missense_variant	Exon 2 of 34	5	NM_003070.5	ENSP00000265773.5		P51531-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

178370

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000141

AC:

AN:

1415106

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

699872

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32110

American (AMR)

AF:

0.00

AC:

AN:

38436

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25366

East Asian (EAS)

AF:

0.00

AC:

AN:

36952

South Asian (SAS)

AF:

0.00

AC:

AN:

81232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50240

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5442

European-Non Finnish (NFE)

AF:

0.00000184

AC:

AN:

1086800

Other (OTH)

AF:

0.00

AC:

AN:

58528

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

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

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

(source)

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

LIST_S2

Uncertain

0.95

.;D;.;.;.;D;D;D;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.50

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.64

MutationAssessor

Benign

1.8

L;.;.;L;.;.;.;L;.;.;L

PhyloP100

6.2

PrimateAI

Pathogenic

0.88

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

GERP RS

5.4

Varity_R

0.38

gMVP

0.26

Mutation Taster

=16/84

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over