rs2303062

Variant names:

• chr5-148100444-A-G
• rs2303062
• NM_006846.4:c.1093-10A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-148100444-A-G
• chr5-148100444-A-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006846.4(SPINK5):​c.1093-10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 1,585,766 control chromosomes in the GnomAD database, including 212,251 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (16479 hom., cov: 31)
  • Exomes 𝑓: 0.51 (195772 hom.)
• Consequence: SPINK5 NM_006846.4 intron
• Scores: Splicing: ADA: 0.000009610
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -8.18
• Publications: 11 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 (BayesDel_noAF=-1.03).
• BP6: Variant 5-148100444-A-G is Benign according to our data. Variant chr5-148100444-A-G is described in ClinVar as Benign. ClinVar VariationId is 260042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

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.1093-10A>G		intron	N/A	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.1093-10A>G		intron	N/A	NP_001121170.1	Q9NQ38-3
	SPINK5	NM_001127699.2		c.1093-10A>G		intron	N/A	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.1093-10A>G		intron	N/A	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.1093-10A>G		intron	N/A	ENSP00000352936.3	Q9NQ38-3
	SPINK5	ENST00000398454.5	TSL:1	c.1093-10A>G		intron	N/A	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67832 AN: 151736 Hom.: 16469 Cov.: 31

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.580

Gnomad ASJ AF: 0.453

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.491

Gnomad FIN AF: 0.534

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.524

Gnomad OTH AF: 0.472

GnomAD2 exomes AF: 0.520 AC: 129131 AN: 248524 AF XY: 0.518

Gnomad AFR exome AF: 0.238

Gnomad AMR exome AF: 0.700

Gnomad ASJ exome AF: 0.462

Gnomad EAS exome AF: 0.474

Gnomad FIN exome AF: 0.547

Gnomad NFE exome AF: 0.519

Gnomad OTH exome AF: 0.522

GnomAD4 exome AF: 0.514 AC: 737158 AN: 1433912 Hom.: 195772 Cov.: 37 AF XY: 0.513 AC XY: 366678 AN XY: 714656

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.226 AC: 7472 AN: 33058

American (AMR) AF: 0.685 AC: 30477 AN: 44518

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 11922 AN: 25858

East Asian (EAS) AF: 0.447 AC: 17628 AN: 39480

South Asian (SAS) AF: 0.489 AC: 41929 AN: 85800

European-Finnish (FIN) AF: 0.547 AC: 29098 AN: 53172

Middle Eastern (MID) AF: 0.509 AC: 2905 AN: 5710

European-Non Finnish (NFE) AF: 0.521 AC: 565985 AN: 1086934

Other (OTH) AF: 0.501 AC: 29742 AN: 59382

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.447 AC: 67854 AN: 151854 Hom.: 16479 Cov.: 31 AF XY: 0.451 AC XY: 33422 AN XY: 74182

African (AFR) AF: 0.237 AC: 9842 AN: 41452

American (AMR) AF: 0.581 AC: 8843 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.453 AC: 1570 AN: 3464

East Asian (EAS) AF: 0.474 AC: 2435 AN: 5136

South Asian (SAS) AF: 0.492 AC: 2368 AN: 4816

European-Finnish (FIN) AF: 0.534 AC: 5604 AN: 10502

Middle Eastern (MID) AF: 0.497 AC: 145 AN: 292

European-Non Finnish (NFE) AF: 0.524 AC: 35583 AN: 67944

Other (OTH) AF: 0.475 AC: 1001 AN: 2108

Alfa AF: 0.493 Hom.: 26518

Bravo AF: 0.445

Asia WGS AF: 0.520 AC: 1803 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Netherton syndrome (2)
-	-	1	Ichthyosis linearis circumflexa (1)
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.0010
DANN	Benign	0.20
PhyloP100		-8.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000096
dbscSNV1_RF	Benign	0.0080
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: rs2303062; hg19: chr5-147480007; COSMIC: COSV56248166; COSMIC: COSV56248166;