rs1555221275

Variant names:

• chr12-56172427-C-A
• rs1555221275
• NM_001330288.2:c.1926+1G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-56172427-C-A
• chr12-56172427-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_001330288.2(SMARCC2):​c.1926+1G>T variant causes a splice donor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMARCC2 NM_001330288.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 7.27
• Publications: 0 publications found

Genes affected

SMARCC2 (HGNC:11105): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin subfamily c member 2) The protein encoded by this gene is a member of the SWI/SNF family of proteins, whose members display helicase and ATPase activities and which 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 and contains a predicted leucine zipper motif typical of many transcription factors. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

SMARCC2 Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Coffin-Siris syndrome 8

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P

ENSG00000258199 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.016853932 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.4, offset of -38, new splice context is: ctcGTgagt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-56172427-C-A is Pathogenic according to our data. Variant chr12-56172427-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 522824.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330288.2. 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
	SMARCC2	NM_001330288.2	MANE Select	c.1926+1G>T		splice_donor intron	N/A	NP_001317217.1	F8VXC8
	SMARCC2	NM_003075.5		c.1833+1G>T		splice_donor intron	N/A	NP_003066.2
	SMARCC2	NM_001130420.3		c.1926+1G>T		splice_donor intron	N/A	NP_001123892.1	Q8TAQ2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCC2	ENST00000550164.6	TSL:5 MANE Select	c.1926+1G>T		splice_donor intron	N/A	ENSP00000449396.1	F8VXC8
	SMARCC2	ENST00000267064.8	TSL:1	c.1833+1G>T		splice_donor intron	N/A	ENSP00000267064.4	Q8TAQ2-1
	SMARCC2	ENST00000394023.7	TSL:1	c.1926+1G>T		splice_donor intron	N/A	ENSP00000377591.3	Q8TAQ2-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1413812 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 699312

African (AFR) AF: 0.00 AC: 0 AN: 31210

American (AMR) AF: 0.00 AC: 0 AN: 34904

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23412

East Asian (EAS) AF: 0.00 AC: 0 AN: 39180

South Asian (SAS) AF: 0.00 AC: 0 AN: 79474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52158

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5514

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089896

Other (OTH) AF: 0.00 AC: 0 AN: 58064

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	SMARCC2-related BAFopathy (1)
-	1	-	SMARCC2-related disorder (1)
-	-	-	Coffin-Siris syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.3
GERP RS		4.3
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: 39
DS_DL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555221275; hg19: chr12-56566211;