chr17-63832949-G-T

Variant names:

• chr17-63832949-G-T
• rs2144624108
• NM_001098426.2:c.1585C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001098426.2(SMARCD2):​c.1585C>A​(p.Arg529Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000705 in 1,417,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R529C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SMARCD2 NM_001098426.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.50
• Publications: 0 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.758

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCD2	NM_001098426.2	c.1585C>A	p.Arg529Ser	missense_variant	Exon 13 of 13	ENST00000448276.7	NP_001091896.1
SMARCD2	NM_001330440.2	c.1441C>A	p.Arg481Ser	missense_variant	Exon 13 of 13		NP_001317369.1
SMARCD2	NM_001330439.1	c.1360C>A	p.Arg454Ser	missense_variant	Exon 13 of 13		NP_001317368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCD2	ENST00000448276.7	c.1585C>A	p.Arg529Ser	missense_variant	Exon 13 of 13	1	NM_001098426.2	ENSP00000392617.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1417770 Hom.: 0 Cov.: 33 AF XY: 0.00000143 AC XY: 1 AN XY: 701288

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32186

American (AMR) AF: 0.00 AC: 0 AN: 38562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25354

East Asian (EAS) AF: 0.00 AC: 0 AN: 37052

South Asian (SAS) AF: 0.00 AC: 0 AN: 80244

European-Finnish (FIN) AF: 0.0000198 AC: 1 AN: 50538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4108

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090998

Other (OTH) AF: 0.00 AC: 0 AN: 58728

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	28
DANN	Benign	0.93
DEOGEN2	Benign	0.14	T;T;.;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.76	D;D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.2	.;M;.;.
PhyloP100		5.5
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-4.0	.;D;D;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.0010	.;D;D;.
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.62
MutPred		0.66		.;Loss of MoRF binding (P = 0.0245);.;.;
MVP		0.53
MPC		0.88
ClinPred		0.98	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.74
gMVP		0.69

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

Other links and lift over

dbSNP: rs2144624108; hg19: chr17-61910309;