rs376643233

Variant names:

• chr5-148094440-C-T
• rs376643233
• NM_006846.4:c.753C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2 BP6_Very_Strong

The NM_006846.4(SPINK5):​c.753C>T​(p.Gly251Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000862 in 1,612,646 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000089 (0 hom.)
• Consequence: SPINK5 NM_006846.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.89
• Publications: 0 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 -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 5-148094440-C-T is Benign according to our data. Variant chr5-148094440-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 570622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.753C>T	p.Gly251Gly	synonymous	Exon 9 of 33	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.753C>T	p.Gly251Gly	synonymous	Exon 9 of 34	NP_001121170.1	Q9NQ38-3
	SPINK5	NM_001127699.2		c.753C>T	p.Gly251Gly	synonymous	Exon 9 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.753C>T	p.Gly251Gly	synonymous	Exon 9 of 33	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.753C>T	p.Gly251Gly	synonymous	Exon 9 of 34	ENSP00000352936.3	Q9NQ38-3
	SPINK5	ENST00000398454.5	TSL:1	c.753C>T	p.Gly251Gly	synonymous	Exon 9 of 28	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 151988 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000562 AC: 14 AN: 249314 AF XY: 0.0000739

Gnomad AFR exome AF: 0.0000647

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: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000890 AC: 130 AN: 1460658 Hom.: 0 Cov.: 31 AF XY: 0.0000963 AC XY: 70 AN XY: 726680

African (AFR) AF: 0.0000899 AC: 3 AN: 33382

American (AMR) AF: 0.00 AC: 0 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.000113 AC: 126 AN: 1111164

Other (OTH) AF: 0.0000166 AC: 1 AN: 60318

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 151988 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74214

African (AFR) AF: 0.0000724 AC: 3 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15240

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67950

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000119 Hom.: 0

Bravo AF: 0.0000718

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Ichthyosis linearis circumflexa (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	16
DANN	Benign	0.71
PhyloP100		1.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.33		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs376643233; hg19: chr5-147474003;