rs1422991

Variant names:

• chr5-148099222-C-T
• rs1422991
• NM_006846.4:c.1011-12C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006846.4(SPINK5):​c.1011-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.509 in 1,600,236 control chromosomes in the GnomAD database, including 211,794 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16753 hom., cov: 30)
  • Exomes 𝑓: 0.51 (195041 hom.)
• Consequence: SPINK5 NM_006846.4 intron
• Scores: Splicing: ADA: 0.000008578
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.30
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 5-148099222-C-T is Benign according to our data. Variant chr5-148099222-C-T is described in ClinVar as Benign. ClinVar VariationId is 260041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK5	NM_006846.4	c.1011-12C>T		intron_variant	Intron 11 of 32	ENST00000256084.8	NP_006837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8	c.1011-12C>T		intron_variant	Intron 11 of 32	1	NM_006846.4	ENSP00000256084.7

Frequencies

GnomAD3 genomes AF: 0.455 AC: 68996 AN: 151548 Hom.: 16747 Cov.: 30

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.584

Gnomad ASJ AF: 0.455

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.491

Gnomad FIN AF: 0.536

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.524

Gnomad OTH AF: 0.479

GnomAD2 exomes AF: 0.519 AC: 120595 AN: 232304 AF XY: 0.517

Gnomad AFR exome AF: 0.262

Gnomad AMR exome AF: 0.699

Gnomad ASJ exome AF: 0.461

Gnomad EAS exome AF: 0.469

Gnomad FIN exome AF: 0.547

Gnomad NFE exome AF: 0.515

Gnomad OTH exome AF: 0.518

GnomAD4 exome AF: 0.515 AC: 745988 AN: 1448572 Hom.: 195041 Cov.: 32 AF XY: 0.514 AC XY: 369723 AN XY: 719668

African (AFR) AF: 0.254 AC: 8458 AN: 33244

American (AMR) AF: 0.683 AC: 29526 AN: 43226

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 11907 AN: 25820

East Asian (EAS) AF: 0.446 AC: 17503 AN: 39270

South Asian (SAS) AF: 0.489 AC: 41306 AN: 84542

European-Finnish (FIN) AF: 0.547 AC: 28887 AN: 52810

Middle Eastern (MID) AF: 0.510 AC: 2927 AN: 5740

European-Non Finnish (NFE) AF: 0.521 AC: 575342 AN: 1104034

Other (OTH) AF: 0.503 AC: 30132 AN: 59886

GnomAD4 genome AF: 0.455 AC: 69017 AN: 151664 Hom.: 16753 Cov.: 30 AF XY: 0.459 AC XY: 34031 AN XY: 74092

African (AFR) AF: 0.265 AC: 10970 AN: 41384

American (AMR) AF: 0.584 AC: 8884 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 1576 AN: 3464

East Asian (EAS) AF: 0.473 AC: 2411 AN: 5094

South Asian (SAS) AF: 0.492 AC: 2364 AN: 4800

European-Finnish (FIN) AF: 0.536 AC: 5643 AN: 10532

Middle Eastern (MID) AF: 0.497 AC: 145 AN: 292

European-Non Finnish (NFE) AF: 0.524 AC: 35551 AN: 67874

Other (OTH) AF: 0.480 AC: 1010 AN: 2106

Alfa AF: 0.472 Hom.: 3293

Bravo AF: 0.454

Asia WGS AF: 0.519 AC: 1799 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Ichthyosis linearis circumflexa Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Netherton syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.25
DANN	Benign	0.47
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000086
dbscSNV1_RF	Benign	0.0
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: rs1422991; hg19: chr5-147478785; COSMIC: COSV56248849; COSMIC: COSV56248849;