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)
• 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCD2	NM_001098426.2	c.805A>G	p.Asn269Asp	missense_variant	Exon 6 of 13	ENST00000448276.7	NP_001091896.1
SMARCD2	NM_001330440.2	c.661A>G	p.Asn221Asp	missense_variant	Exon 6 of 13		NP_001317369.1
SMARCD2	NM_001330439.1	c.580A>G	p.Asn194Asp	missense_variant	Exon 6 of 13		NP_001317368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCD2	ENST00000448276.7	c.805A>G	p.Asn269Asp	missense_variant	Exon 6 of 13	1	NM_001098426.2	ENSP00000392617.2

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 03, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine with aspartic acid at codon 269 of the SMARCD2 protein (p.Asn269Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with SMARCD2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

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;T;.;T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.72	D;D;D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.5	.;M;.;.
PhyloP100		8.0
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.8	.;D;D;.
REVEL	Uncertain	0.34
Sift	Benign	0.043	.;D;D;.
Sift4G	Benign	0.095	T;T;T;T
Polyphen		0.99	D;D;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;