rs1554623111

Variant names:

• chr9-2081973-T-C
• rs1554623111
• NM_003070.5:c.2326T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3 PP5_Moderate

The NM_003070.5(SMARCA2):​c.2326T>C​(p.Tyr776His) 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. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA2 NM_003070.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.02
• Publications: 0 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_003070.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.773
• PP5: Variant 9-2081973-T-C is Pathogenic according to our data. Variant chr9-2081973-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 521300.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA2	NM_003070.5	c.2326T>C	p.Tyr776His	missense_variant	Exon 15 of 34	ENST00000349721.8	NP_003061.3
SMARCA2	NM_001289396.2	c.2326T>C	p.Tyr776His	missense_variant	Exon 15 of 34		NP_001276325.1
SMARCA2	NM_139045.4	c.2326T>C	p.Tyr776His	missense_variant	Exon 15 of 33		NP_620614.2
SMARCA2	NM_001289397.2	c.2326T>C	p.Tyr776His	missense_variant	Exon 15 of 33		NP_001276326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA2	ENST00000349721.8	c.2326T>C	p.Tyr776His	missense_variant	Exon 15 of 34	5	NM_003070.5	ENSP00000265773.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Oct 04, 2016

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	.;.;D;.;D
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D;.;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	-0.82	N;.;N;N;N
PhyloP100		8.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.2	D;.;D;D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.97	D;.;D;D;D
Vest4		0.76
MutPred		0.73		Gain of disorder (P = 0.1271);Gain of disorder (P = 0.1271);Gain of disorder (P = 0.1271);Gain of disorder (P = 0.1271);Gain of disorder (P = 0.1271);
MVP		0.97
MPC		1.9
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.85
gMVP		0.91
Mutation Taster		=10/90	disease causing (ClinVar)

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: rs1554623111; hg19: chr9-2081973;