Genetic Variant SCNN1D:p.Trp140Arg (chr1-1284044-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001130413.4(SCNN1D):c.418T>C(p.Trp140Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000187 in 1,335,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000023 ( 0 hom., cov: 13)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

SCNN1D
NM_001130413.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.841

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.043106228).

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.418T>C	p.Trp140Arg	missense	Exon 5 of 18	NP_001123885.2	P51172-3
	SCNN1D	NR_037668.3		n.644T>C		non_coding_transcript_exon	Exon 5 of 17

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCNN1D	ENST00000379116.10	TSL:5 MANE Select	c.418T>C	p.Trp140Arg	missense	Exon 5 of 18	ENSP00000368411.5	P51172-3
SCNN1D	ENST00000325425.12	TSL:1	c.124T>C	p.Trp42Arg	missense	Exon 2 of 15	ENSP00000321594.8	P51172-2
SCNN1D	ENST00000379101.8	TSL:1	n.418T>C		non_coding_transcript_exon	Exon 5 of 17	ENSP00000449804.1	F8VWH5

Frequencies

GnomAD3 genomes

AF:

0.0000228

AC:

AN:

87830

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:

0.0000450

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000107

AC:

AN:

93324

AF XY:

0.0000188

show subpopulations

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:

0.0000234

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000184

AC:

AN:

1247324

Hom.:

Cov.:

AF XY:

0.0000196

AC XY:

AN XY:

612664

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24560

American (AMR)

AF:

0.00

AC:

AN:

16168

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20400

East Asian (EAS)

AF:

0.00

AC:

AN:

25822

South Asian (SAS)

AF:

0.00

AC:

AN:

58228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43066

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5098

European-Non Finnish (NFE)

AF:

0.0000219

AC:

AN:

1004018

Other (OTH)

AF:

0.0000200

AC:

AN:

49964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

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:

0.0000228

AC:

AN:

87830

Hom.:

Cov.:

AF XY:

0.0000487

AC XY:

AN XY:

41106

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20786

American (AMR)

AF:

0.00

AC:

AN:

7800

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2470

East Asian (EAS)

AF:

0.00

AC:

AN:

3174

South Asian (SAS)

AF:

0.00

AC:

AN:

2310

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4888

Middle Eastern (MID)

AF:

0.00

AC:

AN:

206

European-Non Finnish (NFE)

AF:

0.0000450

AC:

AN:

44470

Other (OTH)

AF:

0.00

AC:

AN:

1176

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

Age Distribution

Genome 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

Alfa

AF:

0.000105

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

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

0.099

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

6.9

(source)

DANN

Benign

0.34

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0042

LIST_S2

Benign

0.27

M_CAP

Benign

0.0033

MetaRNN

Benign

0.043

MetaSVM

Benign

-1.0

PhyloP100

-0.84

PROVEAN

Benign

-0.060

REVEL

Benign

0.097

Sift

Uncertain

0.0070

Sift4G

Benign

0.061

Vest4

0.080

MutPred

0.19

Gain of phosphorylation at M7 (P = 0.0033)

MVP

0.14

ClinPred

0.057

GERP RS

-2.7

Varity_R

0.10

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over