chr1-1281608-C-A

Variant names:

• chr1-1281608-C-A
• rs1400656116
• NM_001130413.4:c.275C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001130413.4(SCNN1D):​c.275C>A​(p.Thr92Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000579 in 1,382,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: SCNN1D NM_001130413.4 missense, splice_region
• Scores: Splicing: ADA: 0.00005453
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.76

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08510995).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCNN1D	NM_001130413.4	c.275C>A	p.Thr92Lys	missense_variant, splice_region_variant	Exon 3 of 18	ENST00000379116.10	NP_001123885.2
SCNN1D	NR_037668.3	n.501C>A		splice_region_variant, 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.275C>A	p.Thr92Lys	missense_variant, splice_region_variant	Exon 3 of 18	5	NM_001130413.4	ENSP00000368411.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000579 AC: 8 AN: 1382688 Hom.: 0 Cov.: 32 AF XY: 0.00000879 AC XY: 6 AN XY: 682270

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: 0.00000742

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.275C>A (p.T92K) alteration is located in exon 3 (coding exon 3) of the SCNN1D gene. This alteration results from a C to A substitution at nucleotide position 275, causing the threonine (T) at amino acid position 92 to be replaced by a lysine (K). 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	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.9
DANN	Benign	0.40
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-0.97	T
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.087
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.15
MVP		0.19
ClinPred		0.087	T
GERP RS		0.93
Varity_R		0.13
gMVP		0.055

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000055
dbscSNV1_RF	Benign	0.064
SpliceAI score (max)		0.040		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: rs1400656116; hg19: chr1-1216988;