rs1422993

Variant names:

• chr5-148124257-A-C
• rs1422993
• NM_006846.4:c.2666+297A>C

Your query was ambiguous. Multiple possible variants found:

• chr5-148124257-A-C
• chr5-148124257-A-G
• chr5-148124257-A-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006846.4(SPINK5):​c.2666+297A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.786 in 152,136 control chromosomes in the GnomAD database, including 47,027 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.79 (47027 hom., cov: 32)
• Consequence: SPINK5 NM_006846.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.35
• Publications: 5 publications found

Genes affected

SPINK5 (HGNC:15464): (serine peptidase inhibitor Kazal type 5) This gene encodes a multidomain serine protease inhibitor that contains 15 potential inhibitory domains. The encoded preproprotein is proteolytically processed to generate multiple protein products, which may exhibit unique activities and specificities. These proteins may play a role in skin and hair morphogenesis, as well as anti-inflammatory and antimicrobial protection of mucous epithelia. Mutations in this gene may result in Netherton syndrome, a disorder characterized by ichthyosis, defective cornification, and atopy. This gene is present in a gene cluster on chromosome 5. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

FBXO38-DT (HGNC:55589): (FBXO38 divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 5-148124257-A-C is Benign according to our data. Variant chr5-148124257-A-C is described in ClinVar as Benign. ClinVar VariationId is 667633.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.893 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006846.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	NM_006846.4	MANE Select	c.2666+297A>C		intron	N/A	NP_006837.2
	SPINK5	NM_001127698.2		c.2666+297A>C		intron	N/A	NP_001121170.1
	SPINK5	NM_001127699.2		c.2666+297A>C		intron	N/A	NP_001121171.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.2666+297A>C		intron	N/A	ENSP00000256084.7
	SPINK5	ENST00000359874.7	TSL:1	c.2666+297A>C		intron	N/A	ENSP00000352936.3
	SPINK5	ENST00000398454.5	TSL:1	c.2666+297A>C		intron	N/A	ENSP00000381472.1

Frequencies

GnomAD3 genomes AF: 0.786 AC: 119466 AN: 152018 Hom.: 46988 Cov.: 32

Gnomad AFR AF: 0.810

Gnomad AMI AF: 0.651

Gnomad AMR AF: 0.812

Gnomad ASJ AF: 0.752

Gnomad EAS AF: 0.915

Gnomad SAS AF: 0.874

Gnomad FIN AF: 0.785

Gnomad MID AF: 0.755

Gnomad NFE AF: 0.753

Gnomad OTH AF: 0.774

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.786 AC: 119564 AN: 152136 Hom.: 47027 Cov.: 32 AF XY: 0.790 AC XY: 58718 AN XY: 74350

African (AFR) AF: 0.810 AC: 33614 AN: 41508

American (AMR) AF: 0.813 AC: 12425 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.752 AC: 2609 AN: 3468

East Asian (EAS) AF: 0.915 AC: 4729 AN: 5170

South Asian (SAS) AF: 0.873 AC: 4210 AN: 4822

European-Finnish (FIN) AF: 0.785 AC: 8295 AN: 10572

Middle Eastern (MID) AF: 0.747 AC: 218 AN: 292

European-Non Finnish (NFE) AF: 0.754 AC: 51234 AN: 67992

Other (OTH) AF: 0.775 AC: 1639 AN: 2114

Alfa AF: 0.771 Hom.: 62678

Bravo AF: 0.788

Asia WGS AF: 0.883 AC: 3056 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.20
DANN	Benign	0.37
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs1422993; hg19: chr5-147503820;