12-56164654-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_001330288.2(SMARCC2):c.3310G>A(p.Val1104Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000672 in 1,612,444 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (2 hom.)
• Consequence: SMARCC2 NM_001330288.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.443

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 -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SMARCC2
• BP4: Computational evidence support a benign effect (MetaRNN=0.032477587).
• BS2: High AC in GnomAd at 76 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCC2	NM_001330288.2	c.3310G>A	p.Val1104Met	missense_variant	28/29	ENST00000550164.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCC2	ENST00000550164.6	c.3310G>A	p.Val1104Met	missense_variant	28/29	5	NM_001330288.2	A2
	ENST00000553176.1	n.213-2105G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000503 AC: 124 AN: 246356 Hom.: 0 AF XY: 0.000510 AC XY: 68 AN XY: 133304

Gnomad AFR exome AF: 0.0000631

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000430

Gnomad FIN exome AF: 0.0000960

Gnomad NFE exome AF: 0.000898

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000690 AC: 1008 AN: 1460152 Hom.: 2 Cov.: 32 AF XY: 0.000661 AC XY: 480 AN XY: 726302

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000226

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000302

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.000827

Gnomad4 OTH exome AF: 0.000597

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74472

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000700 Hom.: 2

Bravo AF: 0.000706

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000502 AC: 61

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.3217G>A (p.V1073M) alteration is located in exon 27 (coding exon 27) of the SMARCC2 gene. This alteration results from a G to A substitution at nucleotide position 3217, causing the valine (V) at amino acid position 1073 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.0064
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.85	D;D;T;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.032	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.80	N;N;N;N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.32	N;N;N;N
REVEL	Benign	0.075
Sift	Benign	0.062	T;D;D;D
Sift4G	Benign	0.22	T;T;T;T
Polyphen		0.085, 0.21	.;.;B;B
Vest4		0.34
MVP		0.16
MPC		0.15
ClinPred		0.021	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.086

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs145318577; hg19: chr12-56558438;