9-2116037-G-T

Variant names:

• chr9-2116037-G-T
• rs6601
• NM_003070.5:c.3672G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003070.5(SMARCA2):​c.3672G>T​(p.Glu1224Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. E1224K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA2 NM_003070.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.191
• Publications: 15 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: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17807063).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA2	NM_003070.5	c.3672G>T	p.Glu1224Asp	missense_variant	Exon 25 of 34	ENST00000349721.8	NP_003061.3
SMARCA2	NM_001289396.2	c.3672G>T	p.Glu1224Asp	missense_variant	Exon 25 of 34		NP_001276325.1
SMARCA2	NM_139045.4	c.3672G>T	p.Glu1224Asp	missense_variant	Exon 25 of 33		NP_620614.2
SMARCA2	NM_001289397.2	c.3498G>T	p.Glu1166Asp	missense_variant	Exon 25 of 33		NP_001276326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA2	ENST00000349721.8	c.3672G>T	p.Glu1224Asp	missense_variant	Exon 25 of 34	5	NM_003070.5	ENSP00000265773.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	12
DANN	Benign	0.91
DEOGEN2	Benign	0.12	.;.;T;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.97	.;D;.;D;D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	-0.015	N;.;N;N;N
PhyloP100		-0.19
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.090	N;.;N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.59	T;.;T;T;T
Sift4G	Benign	0.68	T;T;T;T;T
Polyphen		0.99	D;.;D;D;D
Vest4		0.58
MutPred		0.29		Loss of solvent accessibility (P = 0.322);.;Loss of solvent accessibility (P = 0.322);Loss of solvent accessibility (P = 0.322);Loss of solvent accessibility (P = 0.322);
MVP		0.72
MPC		1.5
ClinPred		0.056	T
GERP RS		-6.9
Varity_R		0.091
gMVP		0.97
Mutation Taster		=81/19	polymorphism

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: rs6601; hg19: chr9-2116037;