rs1130100

Variant names:

• chr17-63834719-T-C
• rs1130100
• NM_001098426.2:c.805A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001098426.2(SMARCD2):​c.805A>G​(p.Asn269Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,460,454 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: SMARCD2 NM_001098426.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02
• Publications: 1 publications found

Genes affected

SMARCD2 (HGNC:11107): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily d, 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 has sequence similarity to the yeast Swp73 protein. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

SMARCD2 Gene-Disease associations (from GenCC):

• specific granule deficiency 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• specific granule deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098426.2. 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
	SMARCD2	NM_001098426.2	MANE Select	c.805A>G	p.Asn269Asp	missense	Exon 6 of 13	NP_001091896.1	Q92925-1
	SMARCD2	NM_001330440.2		c.661A>G	p.Asn221Asp	missense	Exon 6 of 13	NP_001317369.1	Q92925-3
	SMARCD2	NM_001330439.1		c.580A>G	p.Asn194Asp	missense	Exon 6 of 13	NP_001317368.1	J3KMX2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCD2	ENST00000448276.7	TSL:1 MANE Select	c.805A>G	p.Asn269Asp	missense	Exon 6 of 13	ENSP00000392617.2	Q92925-1
	SMARCD2	ENST00000225742.13	TSL:1	c.580A>G	p.Asn194Asp	missense	Exon 6 of 13	ENSP00000225742.9	J3KMX2
	SMARCD2	ENST00000934855.1		c.805A>G	p.Asn269Asp	missense	Exon 6 of 13	ENSP00000604914.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 249208 AF XY: 0.00000740

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1460454 Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21 AN XY: 726614

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1110718

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000620 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	27
DANN	Benign	0.95
DEOGEN2	Benign	0.11	T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.34
Sift	Benign	0.043	D
Sift4G	Benign	0.095	T
Polyphen		0.99	D
Vest4		0.81
MutPred		0.46		Gain of disorder (P = 0.1053)
MVP		0.41
MPC		1.7
ClinPred		0.92	D
GERP RS		5.5
PromoterAI		0.049	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.74
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1130100; hg19: chr17-61912079;