Genetic Variant SCNN1D:p.Thr191Lys (chr1-1285939-C-A) – 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.572C>A(p.Thr191Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,396,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign 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. T191M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SCNN1D
NM_001130413.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.845

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=0.036716342).

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.572C>A	p.Thr191Lys	missense	Exon 7 of 18	NP_001123885.2	P51172-3
	SCNN1D	NR_037668.3		n.704C>A		non_coding_transcript_exon	Exon 6 of 17

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCNN1D	ENST00000379116.10	TSL:5 MANE Select	c.572C>A	p.Thr191Lys	missense	Exon 7 of 18	ENSP00000368411.5	P51172-3
SCNN1D	ENST00000325425.12	TSL:1	c.278C>A	p.Thr93Lys	missense	Exon 4 of 15	ENSP00000321594.8	P51172-2
SCNN1D	ENST00000379101.8	TSL:1	n.478C>A		non_coding_transcript_exon	Exon 6 of 17	ENSP00000449804.1	F8VWH5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1396866

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

688272

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

31974

American (AMR)

AF:

0.00

AC:

AN:

40610

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23946

East Asian (EAS)

AF:

0.00

AC:

AN:

36936

South Asian (SAS)

AF:

0.00

AC:

AN:

78838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43852

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5632

European-Non Finnish (NFE)

AF:

9.28e-7

AC:

AN:

1077468

Other (OTH)

AF:

0.0000174

AC:

AN:

57610

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

2.5

(source)

DANN

Benign

0.79

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0059

LIST_S2

Benign

0.43

M_CAP

Benign

0.0054

MetaRNN

Benign

0.037

MetaSVM

Benign

-0.71

MutationAssessor

Benign

0.34

PhyloP100

-0.84

PrimateAI

Benign

0.41

PROVEAN

Benign

0.61

REVEL

Benign

0.086

Sift

Benign

0.095

Sift4G

Benign

0.090

Vest4

0.20

MutPred

0.22

Loss of phosphorylation at T191 (P = 0.0019)

MVP

0.18

ClinPred

0.48

GERP RS

-0.80

Varity_R

0.032

gMVP

0.13

Mutation Taster

=98/2

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over