5-148120107-C-T

Variant names:

• chr5-148120107-C-T
• rs33920397
• NM_006846.4:c.2412C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_Moderate BP6_Very_Strong BA1

The NM_006846.4(SPINK5):​c.2412C>T​(p.Gly804Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 1,612,934 control chromosomes in the GnomAD database, including 295,935 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (23520 hom., cov: 33)
  • Exomes 𝑓: 0.61 (272415 hom.)
• Consequence: SPINK5 NM_006846.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.619
• Publications: 20 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 -14 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 5-148120107-C-T is Benign according to our data. Variant chr5-148120107-C-T is described in ClinVar as Benign. ClinVar VariationId is 260051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.63 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	NM_006846.4	MANE Select	c.2412C>T	p.Gly804Gly	synonymous	Exon 25 of 33	NP_006837.2
	SPINK5	NM_001127698.2		c.2412C>T	p.Gly804Gly	synonymous	Exon 25 of 34	NP_001121170.1
	SPINK5	NM_001127699.2		c.2412C>T	p.Gly804Gly	synonymous	Exon 25 of 28	NP_001121171.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.2412C>T	p.Gly804Gly	synonymous	Exon 25 of 33	ENSP00000256084.7
	SPINK5	ENST00000359874.7	TSL:1	c.2412C>T	p.Gly804Gly	synonymous	Exon 25 of 34	ENSP00000352936.3
	SPINK5	ENST00000398454.5	TSL:1	c.2412C>T	p.Gly804Gly	synonymous	Exon 25 of 28	ENSP00000381472.1

Frequencies

GnomAD3 genomes AF: 0.542 AC: 82396 AN: 151896 Hom.: 23497 Cov.: 33

Gnomad AFR AF: 0.353

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.640

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.505

Gnomad FIN AF: 0.633

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.629

Gnomad OTH AF: 0.545

GnomAD2 exomes AF: 0.594 AC: 147960 AN: 249272 AF XY: 0.589

Gnomad AFR exome AF: 0.349

Gnomad AMR exome AF: 0.742

Gnomad ASJ exome AF: 0.550

Gnomad EAS exome AF: 0.461

Gnomad FIN exome AF: 0.641

Gnomad NFE exome AF: 0.622

Gnomad OTH exome AF: 0.595

GnomAD4 exome AF: 0.607 AC: 886052 AN: 1460920 Hom.: 272415 Cov.: 51 AF XY: 0.604 AC XY: 438690 AN XY: 726778

African (AFR) AF: 0.345 AC: 11561 AN: 33470

American (AMR) AF: 0.726 AC: 32481 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 14367 AN: 26128

East Asian (EAS) AF: 0.437 AC: 17350 AN: 39686

South Asian (SAS) AF: 0.509 AC: 43903 AN: 86226

European-Finnish (FIN) AF: 0.642 AC: 34273 AN: 53408

Middle Eastern (MID) AF: 0.534 AC: 3078 AN: 5768

European-Non Finnish (NFE) AF: 0.624 AC: 693737 AN: 1111168

Other (OTH) AF: 0.585 AC: 35302 AN: 60350

GnomAD4 genome AF: 0.542 AC: 82459 AN: 152014 Hom.: 23520 Cov.: 33 AF XY: 0.542 AC XY: 40297 AN XY: 74300

African (AFR) AF: 0.353 AC: 14641 AN: 41454

American (AMR) AF: 0.641 AC: 9787 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 1874 AN: 3472

East Asian (EAS) AF: 0.470 AC: 2425 AN: 5156

South Asian (SAS) AF: 0.506 AC: 2436 AN: 4816

European-Finnish (FIN) AF: 0.633 AC: 6688 AN: 10572

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.629 AC: 42767 AN: 67958

Other (OTH) AF: 0.546 AC: 1149 AN: 2106

Alfa AF: 0.591 Hom.: 22808

Bravo AF: 0.536

Asia WGS AF: 0.529 AC: 1833 AN: 3478

EpiCase AF: 0.617

EpiControl AF: 0.616

ClinVar

ClinVar submissions as Germline

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	-0.29
CADD	Benign	21
DANN	Benign	0.69
PhyloP100		0.62
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.88		Position offset: -2
DS_DL_spliceai		0.20		Position offset: 29

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

Other links and lift over

dbSNP: rs33920397; hg19: chr5-147499670; COSMIC: COSV56249036; COSMIC: COSV56249036;