NM_006846.4:c.2132G>A

Variant names:

• chr5-148118456-G-A
• rs3777134
• NM_006846.4:c.2132G>A

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.2132G>A​(p.Arg711Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 1,613,600 control chromosomes in the GnomAD database, including 295,948 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (23528 hom., cov: 32)
  • Exomes 𝑓: 0.61 (272420 hom.)
• Consequence: SPINK5 NM_006846.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 1.18
• Publications: 37 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 (MetaRNN=2.2599243E-6).
• BP6: Variant 5-148118456-G-A is Benign according to our data. Variant chr5-148118456-G-A is described in ClinVar as Benign. ClinVar VariationId is 260049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK5	NM_006846.4	c.2132G>A	p.Arg711Gln	missense_variant	Exon 23 of 33	ENST00000256084.8	NP_006837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8	c.2132G>A	p.Arg711Gln	missense_variant	Exon 23 of 33	1	NM_006846.4	ENSP00000256084.7

Frequencies

GnomAD3 genomes AF: 0.543 AC: 82423 AN: 151928 Hom.: 23505 Cov.: 32

Gnomad AFR AF: 0.353

Gnomad AMI AF: 0.591

Gnomad AMR AF: 0.640

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.470

Gnomad SAS AF: 0.505

Gnomad FIN AF: 0.633

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.629

Gnomad OTH AF: 0.545

GnomAD2 exomes AF: 0.594 AC: 148169 AN: 249534 AF XY: 0.589

Gnomad AFR exome AF: 0.349

Gnomad AMR exome AF: 0.742

Gnomad ASJ exome AF: 0.550

Gnomad EAS exome AF: 0.461

Gnomad FIN exome AF: 0.641

Gnomad NFE exome AF: 0.622

Gnomad OTH exome AF: 0.596

GnomAD4 exome AF: 0.606 AC: 886363 AN: 1461554 Hom.: 272420 Cov.: 55 AF XY: 0.604 AC XY: 438856 AN XY: 727090

African (AFR) AF: 0.345 AC: 11562 AN: 33474

American (AMR) AF: 0.726 AC: 32486 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 14366 AN: 26124

East Asian (EAS) AF: 0.437 AC: 17349 AN: 39680

South Asian (SAS) AF: 0.509 AC: 43919 AN: 86252

European-Finnish (FIN) AF: 0.642 AC: 34265 AN: 53404

Middle Eastern (MID) AF: 0.534 AC: 3077 AN: 5766

European-Non Finnish (NFE) AF: 0.624 AC: 694030 AN: 1111754

Other (OTH) AF: 0.585 AC: 35309 AN: 60376

GnomAD4 genome AF: 0.543 AC: 82486 AN: 152046 Hom.: 23528 Cov.: 32 AF XY: 0.542 AC XY: 40310 AN XY: 74308

African (AFR) AF: 0.354 AC: 14657 AN: 41460

American (AMR) AF: 0.640 AC: 9782 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 1872 AN: 3468

East Asian (EAS) AF: 0.469 AC: 2414 AN: 5144

South Asian (SAS) AF: 0.506 AC: 2438 AN: 4820

European-Finnish (FIN) AF: 0.633 AC: 6699 AN: 10580

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.629 AC: 42781 AN: 67984

Other (OTH) AF: 0.546 AC: 1153 AN: 2110

Alfa AF: 0.594 Hom.: 93414

Bravo AF: 0.536

TwinsUK AF: 0.633 AC: 2346

ESP6500AA AF: 0.381 AC: 1456

ESP6500EA AF: 0.616 AC: 5070

ExAC AF: 0.583 AC: 70397

Asia WGS AF: 0.528 AC: 1832 AN: 3478

EpiCase AF: 0.617

EpiControl AF: 0.616

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

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 91% of patients studied by a panel of primary immunodeficiencies. Number of patients: 80. Only high quality variants are reported.

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

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Netherton syndrome Benign:2

Jan 13, 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.

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1 Other:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing.

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Benign	0.0	.;.;.;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.85
LIST_S2	Benign	0.66	T;T;T;T
MetaRNN	Benign	0.0000023	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L;.;L
PhyloP100		1.2
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.0	N;N;N;N
Sift	Benign	0.17	T;T;T;T
Sift4G	Benign	0.17	T;D;T;D
Vest4		0.11
ClinPred		0.0050	T
GERP RS		3.0
Varity_R		0.043
gMVP		0.42
Mutation Taster		=99/1	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: rs3777134; hg19: chr5-147498019; COSMIC: COSV56248983;