1-1281490-G-A

Variant names:

• chr1-1281490-G-A
• rs552813227
• NM_001130413.4:c.157G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001130413.4(SCNN1D):​c.157G>A​(p.Gly53Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,528,380 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 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: SCNN1D NM_001130413.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.478

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050827026).
• BP6: Variant 1-1281490-G-A is Benign according to our data. Variant chr1-1281490-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2412083.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCNN1D	NM_001130413.4	c.157G>A	p.Gly53Arg	missense_variant	Exon 3 of 18	ENST00000379116.10	NP_001123885.2
SCNN1D	NR_037668.3	n.383G>A		non_coding_transcript_exon_variant	Exon 3 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCNN1D	ENST00000379116.10	c.157G>A	p.Gly53Arg	missense_variant	Exon 3 of 18	5	NM_001130413.4	ENSP00000368411.5
SCNN1D	ENST00000379101.8	n.157G>A		non_coding_transcript_exon_variant	Exon 3 of 17	1		ENSP00000449804.1
SCNN1D	ENST00000338555	c.-242G>A		5_prime_UTR_variant	Exon 1 of 15	2		ENSP00000339504.2
SCNN1D	ENST00000400928	c.-242G>A		5_prime_UTR_variant	Exon 2 of 16	5		ENSP00000383717.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000711 AC: 9 AN: 126532 AF XY: 0.0000875

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000212

Gnomad NFE exome AF: 0.0000409

Gnomad OTH exome AF: 0.000256

GnomAD4 exome AF: 0.0000247 AC: 34 AN: 1376232 Hom.: 0 Cov.: 32 AF XY: 0.0000265 AC XY: 18 AN XY: 678542

Gnomad4 AFR exome AF: 0.0000317 AC: 1 AN: 31538

Gnomad4 AMR exome AF: 0.0000857 AC: 3 AN: 35008

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 24566

Gnomad4 EAS exome AF: 0.0000840 AC: 3 AN: 35722

Gnomad4 SAS exome AF: 0.0000257 AC: 2 AN: 77844

Gnomad4 FIN exome AF: 0.0000301 AC: 1 AN: 33248

Gnomad4 NFE exome AF: 0.0000205 AC: 22 AN: 1075090

Gnomad4 Remaining exome AF: 0.0000347 AC: 2 AN: 57556

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74318

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.0000654 AC: 0.0000654193 AN: 0.0000654193

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Sep 17, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.42
DANN	Benign	0.41
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.10
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.056
MutPred		0.16		Gain of MoRF binding (P = 0.0365);
MVP		0.10
ClinPred		0.020	T
GERP RS		-3.4
Varity_R		0.095
gMVP		0.073
Mutation Taster		=99/1	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

Publications

LitVar

Other links and lift over

dbSNP: rs552813227; hg19: chr1-1216870;