chr5-148114434-C-T

Variant names:

• chr5-148114434-C-T
• rs199567491
• NM_006846.4:c.1960C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001127698.2(SPINK5):​c.1960C>T​(p.Arg654Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000317 in 1,613,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R654H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: SPINK5 NM_001127698.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.364
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11972293).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127698.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	NM_006846.4	MANE Select	c.1960C>T	p.Arg654Cys	missense	Exon 21 of 33	NP_006837.2
	SPINK5	NM_001127698.2		c.1960C>T	p.Arg654Cys	missense	Exon 21 of 34	NP_001121170.1
	SPINK5	NM_001127699.2		c.1960C>T	p.Arg654Cys	missense	Exon 21 of 28	NP_001121171.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.1960C>T	p.Arg654Cys	missense	Exon 21 of 33	ENSP00000256084.7
	SPINK5	ENST00000359874.7	TSL:1	c.1960C>T	p.Arg654Cys	missense	Exon 21 of 34	ENSP00000352936.3
	SPINK5	ENST00000398454.5	TSL:1	c.1960C>T	p.Arg654Cys	missense	Exon 21 of 28	ENSP00000381472.1

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000894

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000213 AC: 53 AN: 249356 AF XY: 0.000185

Gnomad AFR exome AF: 0.000904

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000336

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000310 AC: 453 AN: 1461340 Hom.: 0 Cov.: 33 AF XY: 0.000287 AC XY: 209 AN XY: 726996

African (AFR) AF: 0.00134 AC: 45 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.000353 AC: 392 AN: 1111660

Other (OTH) AF: 0.000116 AC: 7 AN: 60356

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.000310 AC XY: 23 AN XY: 74290

African (AFR) AF: 0.000894 AC: 37 AN: 41408

American (AMR) AF: 0.000196 AC: 3 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000336 Hom.: 1

Bravo AF: 0.000510

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00158 AC: 6

ESP6500EA AF: 0.000726 AC: 6

ExAC AF: 0.000306 AC: 37

EpiCase AF: 0.0000545

EpiControl AF: 0.000415

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Netherton syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.033	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.025	N
PhyloP100		0.36
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.24
Sift	Benign	0.088	T
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.48
MVP		0.31
MPC		0.56
ClinPred		0.12	T
GERP RS		4.5
Varity_R		0.089
gMVP		0.47
Mutation Taster		=86/14	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: rs199567491; hg19: chr5-147493997; COSMIC: COSV56255690;