rs2303071

Variant names:

• chr5-148108804-C-T
• rs2303071
• NM_006846.4:c.1659C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-148108804-C-T
• chr5-148108804-C-A
• chr5-148108804-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006846.4(SPINK5):​c.1659C>T​(p.Val553Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.537 in 1,610,638 control chromosomes in the GnomAD database, including 236,252 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27940 hom., cov: 31)
  • Exomes 𝑓: 0.53 (208312 hom.)
• Consequence: SPINK5 NM_006846.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 0.0280
• Publications: 22 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 5-148108804-C-T is Benign according to our data. Variant chr5-148108804-C-T is described in ClinVar as Benign. ClinVar VariationId is 194856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.028 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.748 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.1659C>T	p.Val553Val	synonymous	Exon 18 of 33	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.1659C>T	p.Val553Val	synonymous	Exon 18 of 34	NP_001121170.1	Q9NQ38-3
	SPINK5	NM_001127699.2		c.1659C>T	p.Val553Val	synonymous	Exon 18 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.1659C>T	p.Val553Val	synonymous	Exon 18 of 33	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.1659C>T	p.Val553Val	synonymous	Exon 18 of 34	ENSP00000352936.3	Q9NQ38-3
	SPINK5	ENST00000398454.5	TSL:1	c.1659C>T	p.Val553Val	synonymous	Exon 18 of 28	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes AF: 0.597 AC: 90622 AN: 151760 Hom.: 27889 Cov.: 31

Gnomad AFR AF: 0.755

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.641

Gnomad ASJ AF: 0.466

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.491

Gnomad FIN AF: 0.536

Gnomad MID AF: 0.545

Gnomad NFE AF: 0.526

Gnomad OTH AF: 0.586

GnomAD2 exomes AF: 0.559 AC: 137754 AN: 246588 AF XY: 0.548

Gnomad AFR exome AF: 0.763

Gnomad AMR exome AF: 0.727

Gnomad ASJ exome AF: 0.473

Gnomad EAS exome AF: 0.475

Gnomad FIN exome AF: 0.548

Gnomad NFE exome AF: 0.521

Gnomad OTH exome AF: 0.544

GnomAD4 exome AF: 0.530 AC: 773849 AN: 1458760 Hom.: 208312 Cov.: 37 AF XY: 0.527 AC XY: 382570 AN XY: 725634

African (AFR) AF: 0.762 AC: 25443 AN: 33374

American (AMR) AF: 0.715 AC: 31903 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.472 AC: 12295 AN: 26040

East Asian (EAS) AF: 0.446 AC: 17644 AN: 39526

South Asian (SAS) AF: 0.490 AC: 42248 AN: 86182

European-Finnish (FIN) AF: 0.547 AC: 29078 AN: 53170

Middle Eastern (MID) AF: 0.539 AC: 3091 AN: 5740

European-Non Finnish (NFE) AF: 0.522 AC: 579773 AN: 1109872

Other (OTH) AF: 0.538 AC: 32374 AN: 60226

GnomAD4 genome AF: 0.597 AC: 90730 AN: 151878 Hom.: 27940 Cov.: 31 AF XY: 0.597 AC XY: 44309 AN XY: 74228

African (AFR) AF: 0.755 AC: 31307 AN: 41440

American (AMR) AF: 0.641 AC: 9769 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.466 AC: 1616 AN: 3466

East Asian (EAS) AF: 0.475 AC: 2448 AN: 5150

South Asian (SAS) AF: 0.493 AC: 2372 AN: 4814

European-Finnish (FIN) AF: 0.536 AC: 5651 AN: 10546

Middle Eastern (MID) AF: 0.524 AC: 153 AN: 292

European-Non Finnish (NFE) AF: 0.526 AC: 35714 AN: 67910

Other (OTH) AF: 0.588 AC: 1238 AN: 2106

Alfa AF: 0.552 Hom.: 35823

Bravo AF: 0.617

Asia WGS AF: 0.554 AC: 1922 AN: 3476

EpiCase AF: 0.521

EpiControl AF: 0.533

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	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	-0.63
CADD	Benign	3.1
DANN	Benign	0.65
PhyloP100		0.028
Mutation Taster		=100/0	polymorphism (auto)

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: rs2303071; hg19: chr5-147488367; COSMIC: COSV56248949;