NM_006846.4:c.2313+31C>G

Variant names:

• chr5-148119089-C-G
• rs9325073
• NM_006846.4:c.2313+31C>G

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.2313+31C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.77 in 1,603,952 control chromosomes in the GnomAD database, including 476,989 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (48085 hom., cov: 31)
  • Exomes 𝑓: 0.77 (428904 hom.)
• Consequence: SPINK5 NM_006846.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0540
• Publications: 12 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=-0.93).
• BP6: Variant 5-148119089-C-G is Benign according to our data. Variant chr5-148119089-C-G is described in ClinVar as Benign. ClinVar VariationId is 1182656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.893 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK5	NM_006846.4	c.2313+31C>G		intron_variant	Intron 24 of 32	ENST00000256084.8	NP_006837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINK5	ENST00000256084.8	c.2313+31C>G		intron_variant	Intron 24 of 32	1	NM_006846.4	ENSP00000256084.7

Frequencies

GnomAD3 genomes AF: 0.794 AC: 120749 AN: 152062 Hom.: 48038 Cov.: 31

Gnomad AFR AF: 0.838

Gnomad AMI AF: 0.652

Gnomad AMR AF: 0.817

Gnomad ASJ AF: 0.751

Gnomad EAS AF: 0.915

Gnomad SAS AF: 0.874

Gnomad FIN AF: 0.784

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.753

Gnomad OTH AF: 0.783

GnomAD2 exomes AF: 0.806 AC: 199230 AN: 247242 AF XY: 0.803

Gnomad AFR exome AF: 0.844

Gnomad AMR exome AF: 0.881

Gnomad ASJ exome AF: 0.771

Gnomad EAS exome AF: 0.922

Gnomad FIN exome AF: 0.788

Gnomad NFE exome AF: 0.750

Gnomad OTH exome AF: 0.780

GnomAD4 exome AF: 0.767 AC: 1113398 AN: 1451772 Hom.: 428904 Cov.: 27 AF XY: 0.769 AC XY: 556133 AN XY: 723002

African (AFR) AF: 0.838 AC: 27893 AN: 33280

American (AMR) AF: 0.871 AC: 38916 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.766 AC: 19959 AN: 26054

East Asian (EAS) AF: 0.910 AC: 36055 AN: 39616

South Asian (SAS) AF: 0.866 AC: 74471 AN: 85988

European-Finnish (FIN) AF: 0.791 AC: 42109 AN: 53264

Middle Eastern (MID) AF: 0.747 AC: 4295 AN: 5750

European-Non Finnish (NFE) AF: 0.746 AC: 823424 AN: 1103076

Other (OTH) AF: 0.770 AC: 46276 AN: 60066

GnomAD4 genome AF: 0.794 AC: 120853 AN: 152180 Hom.: 48085 Cov.: 31 AF XY: 0.798 AC XY: 59347 AN XY: 74380

African (AFR) AF: 0.838 AC: 34808 AN: 41530

American (AMR) AF: 0.817 AC: 12493 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.751 AC: 2607 AN: 3470

East Asian (EAS) AF: 0.915 AC: 4724 AN: 5164

South Asian (SAS) AF: 0.873 AC: 4207 AN: 4818

European-Finnish (FIN) AF: 0.784 AC: 8311 AN: 10596

Middle Eastern (MID) AF: 0.741 AC: 218 AN: 294

European-Non Finnish (NFE) AF: 0.753 AC: 51234 AN: 67998

Other (OTH) AF: 0.784 AC: 1658 AN: 2114

Alfa AF: 0.731 Hom.: 4623

Bravo AF: 0.797

Asia WGS AF: 0.884 AC: 3071 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

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 97% of patients studied by a panel of primary immunodeficiencies. Number of patients: 85. Only high quality variants are reported. -

Netherton syndrome Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.93
CADD	Benign	4.3
DANN	Benign	0.24
PhyloP100		-0.054
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: rs9325073; hg19: chr5-147498652;