Genetic Variant SCNN1D:p.Arg41Gln (chr1-1281455-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001130413.4(SCNN1D):c.122G>A(p.Arg41Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000145 in 1,519,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

SCNN1D
NM_001130413.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.00200

Publications

0 publications found

Variant links:

Genes affected

SCNN1D (HGNC:10601): (sodium channel epithelial 1 subunit delta) Predicted to enable ligand-gated sodium channel activity. Predicted to be involved in sodium ion transmembrane transport. Located in actin cytoskeleton and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

SCNN1D links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03588581).

BP6

Variant 1-1281455-G-A is Benign according to our data. Variant chr1-1281455-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3316654.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130413.4. 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
	SCNN1D	NM_001130413.4	MANE Select	c.122G>A	p.Arg41Gln	missense	Exon 3 of 18	NP_001123885.2	P51172-3
	SCNN1D	NR_037668.3		n.348G>A		non_coding_transcript_exon	Exon 3 of 17

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCNN1D	ENST00000379116.10	TSL:5 MANE Select	c.122G>A	p.Arg41Gln	missense	Exon 3 of 18	ENSP00000368411.5	P51172-3
SCNN1D	ENST00000379101.8	TSL:1	n.122G>A		non_coding_transcript_exon	Exon 3 of 17	ENSP00000449804.1	F8VWH5
SCNN1D	ENST00000338555.6	TSL:2	c.-277G>A		5_prime_UTR	Exon 1 of 15	ENSP00000339504.2	P51172-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000167

AC:

AN:

119430

AF XY:

0.0000155

show subpopulations

Gnomad AFR exome

AF:

0.000158

Gnomad AMR exome

AF:

0.0000434

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:

0.0000132

AC:

AN:

1367582

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

673156

show subpopulations

African (AFR)

AF:

0.0000955

AC:

AN:

31398

American (AMR)

AF:

0.0000290

AC:

AN:

34496

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23772

East Asian (EAS)

AF:

0.00

AC:

AN:

35608

South Asian (SAS)

AF:

0.0000131

AC:

AN:

76528

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32916

Middle Eastern (MID)

AF:

0.000357

AC:

AN:

5598

European-Non Finnish (NFE)

AF:

0.00000934

AC:

AN:

1070102

Other (OTH)

AF:

0.0000175

AC:

AN:

57164

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.0000263

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68024

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000495

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

1.2

(source)

DANN

Benign

0.44

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.00098

LIST_S2

Benign

0.34

M_CAP

Benign

0.0037

MetaRNN

Benign

0.036

MetaSVM

Benign

-0.98

PhyloP100

-0.0020

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.080

REVEL

Benign

0.12

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.047

MutPred

0.093

Loss of glycosylation at T39 (P = 0.0886)

MVP

0.10

ClinPred

0.0074

GERP RS

0.28

PromoterAI

0.0092

Neutral

(source)

Varity_R

0.061

gMVP

0.020

Mutation Taster

=299/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over