Variant 1-1281554-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001130413.4(SCNN1D):c.221T>C(p.Val74Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000521 in 1,535,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000051 ( 0 hom. )

Consequence

SCNN1D
NM_001130413.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.121

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06560886).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCNN1D	NM_001130413.4 link	c.221T>C	p.Val74Ala	missense_variant	Exon 3 of 18	ENST00000379116.10	NP_001123885.2	P51172-3
SCNN1D	NR_037668.3 link	n.447T>C		non_coding_transcript_exon_variant	Exon 3 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCNN1D	ENST00000379116.10 link	c.221T>C	p.Val74Ala	missense_variant	Exon 3 of 18	5	NM_001130413.4	ENSP00000368411.5	P51172-3
SCNN1D	ENST00000379101.8 link	n.221T>C		non_coding_transcript_exon_variant	Exon 3 of 17	1		ENSP00000449804.1	F8VWH5
SCNN1D	ENST00000338555 link	c.-178T>C		5_prime_UTR_variant	Exon 1 of 15	2		ENSP00000339504.2	P51172-1
SCNN1D	ENST00000400928 link	c.-178T>C		5_prime_UTR_variant	Exon 2 of 16	5		ENSP00000383717.3	P51172-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152216

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

GnomAD4 exome

AF:

0.00000506

AC:

AN:

1383466

Hom.:

Cov.:

AF XY:

0.00000439

AC XY:

AN XY:

682650

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000649

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2024

The c.221T>C (p.V74A) alteration is located in exon 3 (coding exon 3) of the SCNN1D gene. This alteration results from a T to C substitution at nucleotide position 221, causing the valine (V) at amino acid position 74 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

2.5

DANN

Benign

0.43

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.082

LIST_S2

Benign

0.17

M_CAP

Benign

0.010

MetaRNN

Benign

0.066

MetaSVM

Benign

-0.97

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.050

REVEL

Benign

0.049

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.14

MutPred

0.30

Loss of sheet (P = 0.0054);

MVP

0.14

ClinPred

0.048

GERP RS

-0.64

Varity_R

0.089

gMVP

0.044

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over