rs142558269

Variant names:

• chr5-148095825-C-T
• rs142558269
• NM_006846.4:c.802C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-148095825-C-T
• chr5-148095825-C-A
• chr5-148095825-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006846.4(SPINK5):​c.802C>T​(p.Arg268Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00843 in 1,611,294 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R268H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0059 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0087 (65 hom.)
• Consequence: SPINK5 NM_006846.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:12
• Conservation: PhyloP100: 1.04
• Publications: 10 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=0.010680467).
• BP6: Variant 5-148095825-C-T is Benign according to our data. Variant chr5-148095825-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 351519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0059 (896/151810) while in subpopulation SAS AF = 0.00935 (45/4812). AF 95% confidence interval is 0.00824. There are 5 homozygotes in GnomAd4. There are 420 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	NM_006846.4	MANE Select	c.802C>T	p.Arg268Cys	missense	Exon 10 of 33	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.802C>T	p.Arg268Cys	missense	Exon 10 of 34	NP_001121170.1	Q9NQ38-3
	SPINK5	NM_001127699.2		c.802C>T	p.Arg268Cys	missense	Exon 10 of 28	NP_001121171.1	Q9NQ38-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.802C>T	p.Arg268Cys	missense	Exon 10 of 33	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.802C>T	p.Arg268Cys	missense	Exon 10 of 34	ENSP00000352936.3	Q9NQ38-3
	SPINK5	ENST00000398454.5	TSL:1	c.802C>T	p.Arg268Cys	missense	Exon 10 of 28	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes AF: 0.00591 AC: 896 AN: 151692 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00631

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00914

Gnomad FIN AF: 0.00322

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00882

Gnomad OTH AF: 0.00768

GnomAD2 exomes AF: 0.00659 AC: 1642 AN: 249024 AF XY: 0.00737

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00387

Gnomad ASJ exome AF: 0.0170

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.00307

Gnomad NFE exome AF: 0.00795

Gnomad OTH exome AF: 0.00878

GnomAD4 exome AF: 0.00869 AC: 12690 AN: 1459484 Hom.: 65 Cov.: 35 AF XY: 0.00870 AC XY: 6316 AN XY: 726120

African (AFR) AF: 0.00171 AC: 57 AN: 33368

American (AMR) AF: 0.00455 AC: 203 AN: 44570

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 382 AN: 26054

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39618

South Asian (SAS) AF: 0.0105 AC: 907 AN: 86204

European-Finnish (FIN) AF: 0.00317 AC: 169 AN: 53364

Middle Eastern (MID) AF: 0.00890 AC: 51 AN: 5732

European-Non Finnish (NFE) AF: 0.00934 AC: 10367 AN: 1110336

Other (OTH) AF: 0.00915 AC: 551 AN: 60238

GnomAD4 genome AF: 0.00590 AC: 896 AN: 151810 Hom.: 5 Cov.: 32 AF XY: 0.00566 AC XY: 420 AN XY: 74172

African (AFR) AF: 0.00147 AC: 61 AN: 41408

American (AMR) AF: 0.00624 AC: 95 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 46 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00935 AC: 45 AN: 4812

European-Finnish (FIN) AF: 0.00322 AC: 34 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00882 AC: 599 AN: 67894

Other (OTH) AF: 0.00760 AC: 16 AN: 2104

Alfa AF: 0.00776 Hom.: 6

Bravo AF: 0.00652

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.0112 AC: 43

ESP6500AA AF: 0.00110 AC: 4

ESP6500EA AF: 0.00910 AC: 74

ExAC AF: 0.00652 AC: 787

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.00802

EpiControl AF: 0.00884

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Netherton syndrome (5)
-	-	5	not provided (5)
-	-	1	Ichthyosis linearis circumflexa (1)
-	-	1	SPINK5-related disorder (1)
-	1	-	Susceptibility to nonsyndromic otitis media (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.061
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.0
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.23
MVP		0.39
MPC		0.51
ClinPred		0.017	T
GERP RS		3.8
Varity_R		0.45
gMVP		0.41
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs142558269; hg19: chr5-147475388;