Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2PM5PP3_StrongPP5_Moderate

The NM_003070.5(SMARCA2):c.2264A>G(p.Lys755Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 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. K755N) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

SMARCA2
NM_003070.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 9.32

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

intellectual disability-sparse hair-brachydactyly syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

SMARCA2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-2081912-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2028592.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 9-2081911-A-G is Pathogenic according to our data. Variant chr9-2081911-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 68759.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003070.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SMARCA2	NM_003070.5	MANE Select	c.2264A>G	p.Lys755Arg	missense	Exon 15 of 34	NP_003061.3
SMARCA2	NM_001289396.2		c.2264A>G	p.Lys755Arg	missense	Exon 15 of 34	NP_001276325.1
SMARCA2	NM_139045.4		c.2264A>G	p.Lys755Arg	missense	Exon 15 of 33	NP_620614.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SMARCA2	ENST00000349721.8	TSL:5 MANE Select	c.2264A>G	p.Lys755Arg	missense	Exon 15 of 34	ENSP00000265773.5
SMARCA2	ENST00000382203.5	TSL:1	c.2264A>G	p.Lys755Arg	missense	Exon 15 of 34	ENSP00000371638.1
SMARCA2	ENST00000450198.6	TSL:1	c.2264A>G	p.Lys755Arg	missense	Exon 15 of 33	ENSP00000392081.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.4

MutationAssessor

Pathogenic

4.7

PhyloP100

9.3

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-2.8

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MutPred

0.87

Loss of methylation at K755 (P = 0.0037)

MVP

0.99

MPC

1.9

ClinPred

1.0

GERP RS

5.4

Varity_R

0.94

gMVP

0.98

Mutation Taster

=0/100

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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rs281875203

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over