12-56164534-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Moderate BP6_Very_Strong BS2

The NM_001330288.2(SMARCC2):c.3430C>G(p.Pro1144Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000112 in 1,614,206 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: SMARCC2 NM_001330288.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.45

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SMARCC2
• BP4: Computational evidence support a benign effect (MetaRNN=0.08740932).
• BP6: Variant 12-56164534-G-C is Benign according to our data. Variant chr12-56164534-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2349090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCC2	NM_001330288.2	c.3430C>G	p.Pro1144Ala	missense_variant	28/29	ENST00000550164.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCC2	ENST00000550164.6	c.3430C>G	p.Pro1144Ala	missense_variant	28/29	5	NM_001330288.2	A2
	ENST00000553176.1	n.213-1985C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000107 AC: 27 AN: 251378 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000114 AC: 167 AN: 1461864 Hom.: 1 Cov.: 32 AF XY: 0.000121 AC XY: 88 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000143

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000853 AC: 13 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74502

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000218 Hom.: 0

Bravo AF: 0.000113

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 04, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

SMARCC2: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.39
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0085	T;T
Eigen	Benign	-0.026
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.087	T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.68	D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.050	N;N
REVEL	Benign	0.013
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.15	T;T
Polyphen		0.13	.;B
Vest4		0.46
MVP		0.15
MPC		0.15
ClinPred		0.13	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199731176; hg19: chr12-56558318;