9-2029084-C-A

Variant names:

• chr9-2029084-C-A
• rs776972919
• NM_003070.5:c.62C>A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_003070.5(SMARCA2):​c.62C>A​(p.Pro21His) variant causes a missense change. The variant allele was found at a frequency of 0.00000421 in 1,426,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: SMARCA2 NM_003070.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.98

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 Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant in the SMARCA2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 93 curated pathogenic missense variants (we use a threshold of 10). The gene has 88 curated benign missense variants. Gene score misZ: 5.054 (above the threshold of 3.09). Trascript score misZ: 4.663 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability-sparse hair-brachydactyly syndrome, Coffin-Siris syndrome 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25757).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA2	NM_003070.5	c.62C>A	p.Pro21His	missense_variant	Exon 2 of 34	ENST00000349721.8	NP_003061.3
SMARCA2	NM_001289396.2	c.62C>A	p.Pro21His	missense_variant	Exon 2 of 34		NP_001276325.1
SMARCA2	NM_139045.4	c.62C>A	p.Pro21His	missense_variant	Exon 2 of 33		NP_620614.2
SMARCA2	NM_001289397.2	c.62C>A	p.Pro21His	missense_variant	Exon 2 of 33		NP_001276326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA2	ENST00000349721.8	c.62C>A	p.Pro21His	missense_variant	Exon 2 of 34	5	NM_003070.5	ENSP00000265773.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000512 AC: 1 AN: 195458 Hom.: 0 AF XY: 0.00000949 AC XY: 1 AN XY: 105372

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000421 AC: 6 AN: 1426524 Hom.: 0 Cov.: 32 AF XY: 0.00000566 AC XY: 4 AN XY: 706644

Gnomad4 AFR exome AF: 0.0000308

Gnomad4 AMR exome AF: 0.00

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: 0.00000366

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome Cov.: 33

Alfa AF: 0.000111 Hom.: 0

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.62C>A (p.P21H) alteration is located in exon 2 (coding exon 1) of the SMARCA2 gene. This alteration results from a C to A substitution at nucleotide position 62, causing the proline (P) at amino acid position 21 to be replaced by a histidine (H). 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	0.24
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.077	.;.;T;D;T;T;T;.;T;T;D
Eigen	Benign	-0.0059
Eigen_PC	Benign	0.083
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	.;D;.;.;.;D;D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	1.7	L;.;.;L;.;.;.;L;.;.;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.2	N;D;.;N;.;.;D;N;D;.;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0040	D;D;.;D;.;.;D;D;D;.;D
Sift4G	Benign	0.068	T;T;.;T;.;.;D;T;D;.;T
Polyphen		0.51	P;.;.;B;.;.;.;P;.;.;B
Vest4		0.42
MutPred		0.20		Loss of glycosylation at P21 (P = 0.0323);Loss of glycosylation at P21 (P = 0.0323);Loss of glycosylation at P21 (P = 0.0323);Loss of glycosylation at P21 (P = 0.0323);Loss of glycosylation at P21 (P = 0.0323);Loss of glycosylation at P21 (P = 0.0323);Loss of glycosylation at P21 (P = 0.0323);Loss of glycosylation at P21 (P = 0.0323);Loss of glycosylation at P21 (P = 0.0323);Loss of glycosylation at P21 (P = 0.0323);Loss of glycosylation at P21 (P = 0.0323);
MVP		0.59
MPC		0.052
ClinPred		0.51	D
GERP RS		4.6
Varity_R		0.28
gMVP		0.22

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: rs776972919; hg19: chr9-2029084;