NM_003070.5:c.683A>C

Variant names:

• chr9-2039793-A-C
• rs62534884
• NM_003070.5:c.683A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003070.5(SMARCA2):​c.683A>C​(p.Gln228Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0477 in 1,595,690 control chromosomes in the GnomAD database, including 1,950 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (153 hom., cov: 32)
  • Exomes 𝑓: 0.049 (1797 hom.)
• Consequence: SMARCA2 NM_003070.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.172
• Publications: 8 publications found

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: PanelApp Australia, Orphanet, G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• blepharophimosis-impaired intellectual development syndrome

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001706928).
• BP6: Variant 9-2039793-A-C is Benign according to our data. Variant chr9-2039793-A-C is described in ClinVar as Benign. ClinVar VariationId is 126351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.056 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA2	NM_003070.5	MANE Select	c.683A>C	p.Gln228Pro	missense	Exon 4 of 34	NP_003061.3
	SMARCA2	NM_001289396.2		c.683A>C	p.Gln228Pro	missense	Exon 4 of 34	NP_001276325.1	P51531-1
	SMARCA2	NM_139045.4		c.683A>C	p.Gln228Pro	missense	Exon 4 of 33	NP_620614.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA2	ENST00000349721.8	TSL:5 MANE Select	c.683A>C	p.Gln228Pro	missense	Exon 4 of 34	ENSP00000265773.5	P51531-1
	SMARCA2	ENST00000382203.5	TSL:1	c.683A>C	p.Gln228Pro	missense	Exon 4 of 34	ENSP00000371638.1	P51531-1
	SMARCA2	ENST00000450198.6	TSL:1	c.683A>C	p.Gln228Pro	missense	Exon 4 of 33	ENSP00000392081.2	F6VDE0

Frequencies

GnomAD3 genomes AF: 0.0388 AC: 5892 AN: 151810 Hom.: 153 Cov.: 32

Gnomad AFR AF: 0.00932

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.0412

Gnomad ASJ AF: 0.0646

Gnomad EAS AF: 0.000966

Gnomad SAS AF: 0.0191

Gnomad FIN AF: 0.0388

Gnomad MID AF: 0.0350

Gnomad NFE AF: 0.0575

Gnomad OTH AF: 0.0451

GnomAD2 exomes AF: 0.0400 AC: 9200 AN: 230138 AF XY: 0.0406

Gnomad AFR exome AF: 0.00915

Gnomad AMR exome AF: 0.0340

Gnomad ASJ exome AF: 0.0650

Gnomad EAS exome AF: 0.000527

Gnomad FIN exome AF: 0.0415

Gnomad NFE exome AF: 0.0557

Gnomad OTH exome AF: 0.0497

GnomAD4 exome AF: 0.0487 AC: 70266 AN: 1443764 Hom.: 1797 Cov.: 34 AF XY: 0.0483 AC XY: 34667 AN XY: 718060

African (AFR) AF: 0.00770 AC: 255 AN: 33102

American (AMR) AF: 0.0349 AC: 1530 AN: 43820

Ashkenazi Jewish (ASJ) AF: 0.0613 AC: 1583 AN: 25828

East Asian (EAS) AF: 0.000637 AC: 25 AN: 39258

South Asian (SAS) AF: 0.0194 AC: 1655 AN: 85312

European-Finnish (FIN) AF: 0.0420 AC: 2155 AN: 51250

Middle Eastern (MID) AF: 0.0669 AC: 380 AN: 5678

European-Non Finnish (NFE) AF: 0.0546 AC: 60033 AN: 1099924

Other (OTH) AF: 0.0445 AC: 2650 AN: 59592

GnomAD4 genome AF: 0.0388 AC: 5895 AN: 151926 Hom.: 153 Cov.: 32 AF XY: 0.0371 AC XY: 2757 AN XY: 74254

African (AFR) AF: 0.00929 AC: 385 AN: 41424

American (AMR) AF: 0.0411 AC: 628 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0646 AC: 224 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5164

South Asian (SAS) AF: 0.0194 AC: 93 AN: 4804

European-Finnish (FIN) AF: 0.0388 AC: 411 AN: 10596

Middle Eastern (MID) AF: 0.0377 AC: 11 AN: 292

European-Non Finnish (NFE) AF: 0.0575 AC: 3903 AN: 67896

Other (OTH) AF: 0.0447 AC: 94 AN: 2104

Alfa AF: 0.0465 Hom.: 77

Bravo AF: 0.0379

TwinsUK AF: 0.0359 AC: 133

ALSPAC AF: 0.0506 AC: 195

ExAC AF: 0.0352 AC: 3985

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Nicolaides-Baraitser syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.7
DANN	Benign	0.79
DEOGEN2	Benign	0.022	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.60	N
PhyloP100		0.17
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.048
Sift	Benign	0.50	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.15
MPC		0.054
ClinPred		0.0016	T
GERP RS		-0.30
Varity_R		0.11
gMVP		0.62
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs62534884; hg19: chr9-2039793; COSMIC: COSV61804952; COSMIC: COSV61804952;