rs2400478

Variant names:

• chr5-148131303-T-C
• rs2400478
• NM_006846.4:c.3009T>C

Your query was ambiguous. Multiple possible variants found:

• chr5-148131303-T-C
• chr5-148131303-T-G
• chr5-148131303-T-A

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.3009T>C​(p.Gly1003Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.604 in 1,613,442 control chromosomes in the GnomAD database, including 298,343 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G1003G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.56 (24691 hom., cov: 31)
  • Exomes 𝑓: 0.61 (273652 hom.)
• Consequence: SPINK5 NM_006846.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.314
• Publications: 23 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=-0.57).
• BP6: Variant 5-148131303-T-C is Benign according to our data. Variant chr5-148131303-T-C is described in ClinVar as Benign. ClinVar VariationId is 260055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.314 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.638 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.3009T>C	p.Gly1003Gly	synonymous	Exon 31 of 33	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.3099T>C	p.Gly1033Gly	synonymous	Exon 32 of 34	NP_001121170.1	Q9NQ38-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.3009T>C	p.Gly1003Gly	synonymous	Exon 31 of 33	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.3099T>C	p.Gly1033Gly	synonymous	Exon 32 of 34	ENSP00000352936.3	Q9NQ38-3
	FBXO38-DT	ENST00000667608.1		n.1257-37561A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.562 AC: 85275 AN: 151868 Hom.: 24656 Cov.: 31

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.592

Gnomad AMR AF: 0.649

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.504

Gnomad FIN AF: 0.632

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.629

Gnomad OTH AF: 0.559

GnomAD2 exomes AF: 0.599 AC: 149391 AN: 249530 AF XY: 0.593

Gnomad AFR exome AF: 0.418

Gnomad AMR exome AF: 0.746

Gnomad ASJ exome AF: 0.550

Gnomad EAS exome AF: 0.462

Gnomad FIN exome AF: 0.642

Gnomad NFE exome AF: 0.622

Gnomad OTH exome AF: 0.598

GnomAD4 exome AF: 0.608 AC: 889275 AN: 1461456 Hom.: 273652 Cov.: 51 AF XY: 0.605 AC XY: 440042 AN XY: 727052

African (AFR) AF: 0.414 AC: 13873 AN: 33472

American (AMR) AF: 0.732 AC: 32719 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 14369 AN: 26130

East Asian (EAS) AF: 0.437 AC: 17339 AN: 39670

South Asian (SAS) AF: 0.508 AC: 43782 AN: 86250

European-Finnish (FIN) AF: 0.642 AC: 34263 AN: 53394

Middle Eastern (MID) AF: 0.536 AC: 3092 AN: 5766

European-Non Finnish (NFE) AF: 0.624 AC: 694182 AN: 1111674

Other (OTH) AF: 0.591 AC: 35656 AN: 60376

GnomAD4 genome AF: 0.562 AC: 85359 AN: 151986 Hom.: 24691 Cov.: 31 AF XY: 0.561 AC XY: 41694 AN XY: 74308

African (AFR) AF: 0.420 AC: 17390 AN: 41416

American (AMR) AF: 0.649 AC: 9909 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 1874 AN: 3468

East Asian (EAS) AF: 0.470 AC: 2424 AN: 5162

South Asian (SAS) AF: 0.505 AC: 2437 AN: 4822

European-Finnish (FIN) AF: 0.632 AC: 6672 AN: 10560

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.629 AC: 42779 AN: 67976

Other (OTH) AF: 0.560 AC: 1181 AN: 2108

Alfa AF: 0.601 Hom.: 83704

Bravo AF: 0.558

Asia WGS AF: 0.536 AC: 1858 AN: 3478

EpiCase AF: 0.617

EpiControl AF: 0.616

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	8.2
DANN	Benign	0.70
PhyloP100		0.31
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: rs2400478; hg19: chr5-147510866; COSMIC: COSV56249075;