NM_006846.4:c.2243A>G

Variant names:

• chr5-148118988-A-G
• rs181639116
• NM_006846.4:c.2243A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006846.4(SPINK5):​c.2243A>G​(p.Glu748Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00404 in 1,613,870 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (13 hom.)
• Consequence: SPINK5 NM_006846.4 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: 1.52
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006309241).
• BP6: Variant 5-148118988-A-G is Benign according to our data. Variant chr5-148118988-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 449103.
• BS2: High Homozygotes in GnomAdExome4 at 13 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.2243A>G	p.Glu748Gly	missense splice_region	Exon 24 of 33	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.2243A>G	p.Glu748Gly	missense splice_region	Exon 24 of 34	NP_001121170.1	Q9NQ38-3
	SPINK5	NM_001127699.2		c.2243A>G	p.Glu748Gly	missense splice_region	Exon 24 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.2243A>G	p.Glu748Gly	missense splice_region	Exon 24 of 33	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.2243A>G	p.Glu748Gly	missense splice_region	Exon 24 of 34	ENSP00000352936.3	Q9NQ38-3
	SPINK5	ENST00000398454.5	TSL:1	c.2243A>G	p.Glu748Gly	missense splice_region	Exon 24 of 28	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 453 AN: 152202 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00438

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00292 AC: 727 AN: 249324 AF XY: 0.00273

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.00351

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00264

Gnomad NFE exome AF: 0.00448

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00415 AC: 6065 AN: 1461550 Hom.: 13 Cov.: 34 AF XY: 0.00397 AC XY: 2888 AN XY: 727102

African (AFR) AF: 0.000597 AC: 20 AN: 33476

American (AMR) AF: 0.00347 AC: 155 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.000880 AC: 23 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00335 AC: 179 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00493 AC: 5477 AN: 1111786

Other (OTH) AF: 0.00349 AC: 211 AN: 60382

GnomAD4 genome AF: 0.00297 AC: 453 AN: 152320 Hom.: 1 Cov.: 33 AF XY: 0.00290 AC XY: 216 AN XY: 74486

African (AFR) AF: 0.00101 AC: 42 AN: 41574

American (AMR) AF: 0.00497 AC: 76 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00438 AC: 298 AN: 68024

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00381 Hom.: 3

Bravo AF: 0.00295

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00135 AC: 5

ESP6500EA AF: 0.00524 AC: 43

ExAC AF: 0.00314 AC: 379

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00371

EpiControl AF: 0.00439

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	Netherton syndrome (5)
-	1	2	not provided (3)
-	-	1	Ichthyosis linearis circumflexa (1)
-	1	-	Susceptibility to nonsyndromic otitis media (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.5
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.039
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.023	D
Polyphen		0.31	B
Vest4		0.22
MVP		0.38
MPC		0.23
ClinPred		0.019	T
GERP RS		2.5
Varity_R		0.085
gMVP		0.27
Mutation Taster		=91/9	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: rs181639116; hg19: chr5-147498551;