rs2303068

Positions:

• chr5-148101455-G-A
• chr5-148101455-G-C
• chr5-148101455-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006846.4(SPINK5):​c.1302+19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.505 in 1,571,376 control chromosomes in the GnomAD database, including 205,470 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (16469 hom., cov: 31)
  • Exomes 𝑓: 0.51 (189001 hom.)
• Consequence: SPINK5 NM_006846.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.326

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 5-148101455-G-A is Benign according to our data. Variant chr5-148101455-G-A is described in ClinVar as [Benign]. Clinvar id is 260044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-148101455-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINK5	NM_006846.4	c.1302+19G>A		intron_variant		ENST00000256084.8	NP_006837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8	c.1302+19G>A		intron_variant		1	NM_006846.4	ENSP00000256084	P2
FBXO38-DT	ENST00000667608.1	n.1257-7713C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67780 AN: 151470 Hom.: 16459 Cov.: 31

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.581

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.537

Gnomad MID AF: 0.510

Gnomad NFE AF: 0.524

Gnomad OTH AF: 0.474

GnomAD3 exomes AF: 0.520 AC: 128745 AN: 247788 Hom.: 34841 AF XY: 0.518 AC XY: 69557 AN XY: 134372

Gnomad AFR exome AF: 0.237

Gnomad AMR exome AF: 0.700

Gnomad ASJ exome AF: 0.462

Gnomad EAS exome AF: 0.473

Gnomad SAS exome AF: 0.487

Gnomad FIN exome AF: 0.550

Gnomad NFE exome AF: 0.519

Gnomad OTH exome AF: 0.524

GnomAD4 exome AF: 0.512 AC: 726380 AN: 1419788 Hom.: 189001 Cov.: 26 AF XY: 0.511 AC XY: 362251 AN XY: 708960

Gnomad4 AFR exome AF: 0.228

Gnomad4 AMR exome AF: 0.684

Gnomad4 ASJ exome AF: 0.460

Gnomad4 EAS exome AF: 0.446

Gnomad4 SAS exome AF: 0.488

Gnomad4 FIN exome AF: 0.549

Gnomad4 NFE exome AF: 0.517

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.447 AC: 67802 AN: 151588 Hom.: 16469 Cov.: 31 AF XY: 0.451 AC XY: 33388 AN XY: 73990

Gnomad4 AFR AF: 0.238

Gnomad4 AMR AF: 0.581

Gnomad4 ASJ AF: 0.454

Gnomad4 EAS AF: 0.475

Gnomad4 SAS AF: 0.491

Gnomad4 FIN AF: 0.537

Gnomad4 NFE AF: 0.524

Gnomad4 OTH AF: 0.477

Alfa AF: 0.477 Hom.: 4303

Bravo AF: 0.445

Asia WGS AF: 0.520 AC: 1803 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 89% of patients studied by a panel of primary immunodeficiencies. Number of patients: 78. Only high quality variants are reported. -

Ichthyosis linearis circumflexa Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Netherton syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.12
DANN	Benign	0.22

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: rs2303068; hg19: chr5-147481018; COSMIC: COSV56248208; COSMIC: COSV56248208;