1-1284044-T-A

Variant names:

• chr1-1284044-T-A
• rs1313906782
• NM_001130413.4:c.418T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001130413.4(SCNN1D):​c.418T>A​(p.Trp140Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000802 in 1,247,320 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 13)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: SCNN1D NM_001130413.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.841
• Publications: 0 publications found

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]

ACMG classification

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=0.03917861).

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

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes Cov.: 13

GnomAD4 exome AF: 8.02e-7 AC: 1 AN: 1247320 Hom.: 0 Cov.: 29 AF XY: 0.00000163 AC XY: 1 AN XY: 612662

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

African (AFR) AF: 0.00 AC: 0 AN: 24560

American (AMR) AF: 0.00 AC: 0 AN: 16168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20400

East Asian (EAS) AF: 0.00 AC: 0 AN: 25820

South Asian (SAS) AF: 0.00 AC: 0 AN: 58226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5098

European-Non Finnish (NFE) AF: 9.96e-7 AC: 1 AN: 1004018

Other (OTH) AF: 0.00 AC: 0 AN: 49964

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 13

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	6.8
DANN	Benign	0.70
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.84
PROVEAN	Benign	0.23	N
REVEL	Benign	0.14
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.027	D
Vest4		0.21
MutPred		0.31		Gain of ubiquitination at M7 (P = 0.0045)
MVP		0.15
ClinPred		0.077	T
GERP RS		-2.7
Varity_R		0.10
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs1313906782; hg19: chr1-1219424;