9-2060894-G-A

Position:

• chr9-2060894-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP5

The NM_003070.5(SMARCA2):​c.1600G>A​(p.Asp534Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA2 NM_003070.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP5: Variant 9-2060894-G-A is Pathogenic according to our data. Variant chr9-2060894-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 827769.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA2	NM_003070.5	c.1600G>A	p.Asp534Asn	missense_variant	9/34	ENST00000349721.8	NP_003061.3
SMARCA2	NM_001289396.1	c.1600G>A	p.Asp534Asn	missense_variant	9/34		NP_001276325.1
SMARCA2	NM_139045.4	c.1600G>A	p.Asp534Asn	missense_variant	9/33		NP_620614.2
SMARCA2	NM_001289397.2	c.1600G>A	p.Asp534Asn	missense_variant	9/33		NP_001276326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA2	ENST00000349721.8	c.1600G>A	p.Asp534Asn	missense_variant	9/34	5	NM_003070.5	ENSP00000265773	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Fondazione Telethon, Telethon Institute of Genetics and Medicine

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	.;.;D;.;D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;D;.;D;D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.69	D;D;D;D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.2	M;.;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.6	D;D;D;D;D
REVEL	Uncertain	0.34
Sift	Benign	0.048	D;D;T;D;T
Sift4G	Uncertain	0.024	D;D;D;D;D
Polyphen		1.0	D;.;D;D;D
Vest4		0.73
MutPred		0.37		Gain of MoRF binding (P = 0.0358);Gain of MoRF binding (P = 0.0358);Gain of MoRF binding (P = 0.0358);Gain of MoRF binding (P = 0.0358);Gain of MoRF binding (P = 0.0358);
MVP		0.77
MPC		2.0
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.46
gMVP		0.83

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

LitVar

Other links and lift over

dbSNP: rs863224922; hg19: chr9-2060894;