rs115504632

Variant names:

• chr5-148107109-C-T
• rs115504632
• NM_006846.4:c.1552C>T

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.1552C>T​(p.Arg518Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,613,382 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R518H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0097 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (18 hom.)
• Consequence: SPINK5 NM_006846.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.408
• Publications: 3 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=0.013533473).
• BP6: Variant 5-148107109-C-T is Benign according to our data. Variant chr5-148107109-C-T is described in ClinVar as Benign. ClinVar VariationId is 139260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00969 (1474/152194) while in subpopulation AFR AF = 0.0336 (1394/41542). AF 95% confidence interval is 0.0321. There are 19 homozygotes in GnomAd4. There are 668 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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.1552C>T	p.Arg518Cys	missense	Exon 17 of 33	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.1552C>T	p.Arg518Cys	missense	Exon 17 of 34	NP_001121170.1	Q9NQ38-3
	SPINK5	NM_001127699.2		c.1552C>T	p.Arg518Cys	missense	Exon 17 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.1552C>T	p.Arg518Cys	missense	Exon 17 of 33	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.1552C>T	p.Arg518Cys	missense	Exon 17 of 34	ENSP00000352936.3	Q9NQ38-3
	SPINK5	ENST00000398454.5	TSL:1	c.1552C>T	p.Arg518Cys	missense	Exon 17 of 28	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes AF: 0.00967 AC: 1471 AN: 152076 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0336

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00400

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: 0.000118

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00244 AC: 610 AN: 249520 AF XY: 0.00169

Gnomad AFR exome AF: 0.0344

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000971

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00100 AC: 1467 AN: 1461188 Hom.: 18 Cov.: 29 AF XY: 0.000830 AC XY: 603 AN XY: 726936

African (AFR) AF: 0.0355 AC: 1186 AN: 33448

American (AMR) AF: 0.00197 AC: 88 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39668

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5758

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1111584

Other (OTH) AF: 0.00257 AC: 155 AN: 60344

GnomAD4 genome AF: 0.00969 AC: 1474 AN: 152194 Hom.: 19 Cov.: 32 AF XY: 0.00898 AC XY: 668 AN XY: 74402

African (AFR) AF: 0.0336 AC: 1394 AN: 41542

American (AMR) AF: 0.00399 AC: 61 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68010

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00335 Hom.: 26

Bravo AF: 0.0111

ESP6500AA AF: 0.0255 AC: 103

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00281 AC: 340

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Ichthyosis linearis circumflexa (1)
-	-	1	Netherton syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.045	N
PhyloP100		-0.41
PrimateAI	Benign	0.24	T
PROVEAN	Benign	2.9	N
REVEL	Benign	0.21
Sift	Benign	0.10	T
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.47
MVP		0.27
MPC		0.44
ClinPred		0.033	T
GERP RS		0.77
Varity_R		0.088
gMVP		0.38
Mutation Taster		=93/7	polymorphism

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: rs115504632; hg19: chr5-147486672; COSMIC: COSV56261721;