Genetic Variant SMARCD2:p.Arg276Trp (chr17-63834569-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001098426.2(SMARCD2):c.826C>T(p.Arg276Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,602,584 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.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SMARCD2
NM_001098426.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.288

Publications

2 publications found

Variant links:

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

SMARCD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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, 0.806

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCD2	NM_001098426.2 link	c.826C>T	p.Arg276Trp	missense_variant	Exon 7 of 13	ENST00000448276.7	NP_001091896.1	Q92925-1
SMARCD2	NM_001330440.2 link	c.682C>T	p.Arg228Trp	missense_variant	Exon 7 of 13		NP_001317369.1	Q92925-3
SMARCD2	NM_001330439.1 link	c.601C>T	p.Arg201Trp	missense_variant	Exon 7 of 13		NP_001317368.1	J3KMX2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCD2	ENST00000448276.7 link	c.826C>T	p.Arg276Trp	missense_variant	Exon 7 of 13	1	NM_001098426.2	ENSP00000392617.2		Q92925-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000413

AC:

AN:

241958

AF XY:

0.00000761

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000303

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1450422

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

720338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33126

American (AMR)

AF:

0.0000230

AC:

AN:

43556

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25528

East Asian (EAS)

AF:

0.00

AC:

AN:

39534

South Asian (SAS)

AF:

0.00

AC:

AN:

85516

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53172

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

9.05e-7

AC:

AN:

1104462

Other (OTH)

AF:

0.00

AC:

AN:

59814

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.34

T;T;.;T

Eigen

Benign

0.014

Eigen_PC

Benign

0.027

FATHMM_MKL

Uncertain

0.84

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.81

D;D;D;D

MetaSVM

Uncertain

-0.16

MutationAssessor

Pathogenic

3.5

.;M;.;.

PhyloP100

0.29

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-7.3

.;D;D;.

REVEL

Uncertain

0.46

Sift

Uncertain

0.015

.;D;D;.

Sift4G

Uncertain

0.0090

D;D;D;D

Polyphen

0.074

B;B;D;.

Vest4

0.86

MutPred

0.50

.;Loss of disorder (P = 0.0393);.;.;

MVP

0.68

MPC

1.6

ClinPred

0.87

GERP RS

3.5

PromoterAI

-0.068

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.67

gMVP

0.81

Mutation Taster

=52/48

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over