17-63832989-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001098426.2(SMARCD2):c.1545G>A(p.Val515=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00438 in 1,586,544 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (33 hom.)
• Consequence: SMARCD2 NM_001098426.2 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.174

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 17-63832989-C-T is Benign according to our data. Variant chr17-63832989-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 790464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63832989-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.174 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00272 (415/152316) while in subpopulation NFE AF= 0.00394 (268/68030). AF 95% confidence interval is 0.00355. There are 0 homozygotes in gnomad4. There are 192 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCD2	NM_001098426.2	c.1545G>A	p.Val515=	splice_region_variant, synonymous_variant	13/13	ENST00000448276.7
SMARCD2	NM_001330440.2	c.1401G>A	p.Val467=	splice_region_variant, synonymous_variant	13/13
SMARCD2	NM_001330439.1	c.1320G>A	p.Val440=	splice_region_variant, synonymous_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCD2	ENST00000448276.7	c.1545G>A	p.Val515=	splice_region_variant, synonymous_variant	13/13	1	NM_001098426.2	P1

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 415 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00622

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00394

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00308 AC: 645 AN: 209554 Hom.: 3 AF XY: 0.00324 AC XY: 365 AN XY: 112784

Gnomad AFR exome AF: 0.000601

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00334

Gnomad FIN exome AF: 0.00563

Gnomad NFE exome AF: 0.00409

Gnomad OTH exome AF: 0.00260

GnomAD4 exome AF: 0.00455 AC: 6529 AN: 1434228 Hom.: 33 Cov.: 33 AF XY: 0.00447 AC XY: 3175 AN XY: 710922

Gnomad4 AFR exome AF: 0.000641

Gnomad4 AMR exome AF: 0.00149

Gnomad4 ASJ exome AF: 0.00192

Gnomad4 EAS exome AF: 0.0000261

Gnomad4 SAS exome AF: 0.00403

Gnomad4 FIN exome AF: 0.00494

Gnomad4 NFE exome AF: 0.00508

Gnomad4 OTH exome AF: 0.00349

GnomAD4 genome AF: 0.00272 AC: 415 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.00258 AC XY: 192 AN XY: 74474

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00622

Gnomad4 NFE AF: 0.00394

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00273 Hom.: 0

Bravo AF: 0.00237

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Specific granule deficiency 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 07, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

SMARCD2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 10, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
Cadd	Benign	13
Dann	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs181910740; hg19: chr17-61910349;