5-148120328-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_006846.4(SPINK5):c.2475G>C(p.Glu825Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000312 in 1,603,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

SPINK5
NM_006846.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.623

Publications

38 publications found

Variant links:

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]

SPINK5 links:

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

FBXO38-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.053985775).

BP6

Variant 5-148120328-G-C is Benign according to our data. Variant chr5-148120328-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1610772.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPINK5	NM_006846.4	MANE Select	c.2475G>C	p.Glu825Asp	missense	Exon 26 of 33	NP_006837.2
SPINK5	NM_001127698.2		c.2475G>C	p.Glu825Asp	missense	Exon 26 of 34	NP_001121170.1
SPINK5	NM_001127699.2		c.2475G>C	p.Glu825Asp	missense	Exon 26 of 28	NP_001121171.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.2475G>C	p.Glu825Asp	missense	Exon 26 of 33	ENSP00000256084.7
SPINK5	ENST00000359874.7	TSL:1	c.2475G>C	p.Glu825Asp	missense	Exon 26 of 34	ENSP00000352936.3
SPINK5	ENST00000398454.5	TSL:1	c.2475G>C	p.Glu825Asp	missense	Exon 26 of 28	ENSP00000381472.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151918

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1451798

Hom.:

Cov.:

AF XY:

0.00000416

AC XY:

AN XY:

720918

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33172

American (AMR)

AF:

0.00

AC:

AN:

43758

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25956

East Asian (EAS)

AF:

0.00

AC:

AN:

39288

South Asian (SAS)

AF:

0.00

AC:

AN:

84486

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52856

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000361

AC:

AN:

1106504

Other (OTH)

AF:

0.00

AC:

AN:

60020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151918

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74190

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41366

American (AMR)

AF:

0.00

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67982

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

3438

Bravo

AF:

0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Ichthyosis linearis circumflexa

Benign:1

Oct 14, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

3.9

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.46

M_CAP

Benign

0.0040

MetaRNN

Benign

0.054

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.0

PhyloP100

-0.62

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.77

REVEL

Benign

0.040

Sift

Benign

0.14

Sift4G

Benign

0.15

Polyphen

0.016

Vest4

0.086

MutPred

0.14

Loss of methylation at K824 (P = 0.086)

MVP

0.29

MPC

0.11

ClinPred

0.12

GERP RS

0.56

Varity_R

0.10

gMVP

0.23

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over