chr5-148118448-T-C

Variant names:

• chr5-148118448-T-C
• rs200884153
• NM_006846.4:c.2124T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_006846.4(SPINK5):​c.2124T>C​(p.Ala708Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000579 in 1,614,040 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00058 (0 hom.)
• Consequence: SPINK5 NM_006846.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.0680
• Publications: 1 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 5-148118448-T-C is Benign according to our data. Variant chr5-148118448-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 389979.
• BP7: Synonymous conserved (PhyloP=-0.068 with no splicing effect.

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.2124T>C	p.Ala708Ala	synonymous	Exon 23 of 33	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.2124T>C	p.Ala708Ala	synonymous	Exon 23 of 34	NP_001121170.1	Q9NQ38-3
	SPINK5	NM_001127699.2		c.2124T>C	p.Ala708Ala	synonymous	Exon 23 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.2124T>C	p.Ala708Ala	synonymous	Exon 23 of 33	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.2124T>C	p.Ala708Ala	synonymous	Exon 23 of 34	ENSP00000352936.3	Q9NQ38-3
	SPINK5	ENST00000398454.5	TSL:1	c.2124T>C	p.Ala708Ala	synonymous	Exon 23 of 28	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000501 AC: 125 AN: 249568 AF XY: 0.000465

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000953

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000581 AC: 849 AN: 1461822 Hom.: 0 Cov.: 33 AF XY: 0.000637 AC XY: 463 AN XY: 727218

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.000262 AC: 14 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000713 AC: 793 AN: 1111964

Other (OTH) AF: 0.000447 AC: 27 AN: 60394

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.000471 AC XY: 35 AN XY: 74354

African (AFR) AF: 0.0000724 AC: 3 AN: 41450

American (AMR) AF: 0.000720 AC: 11 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000985 AC: 67 AN: 68044

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000688 Hom.: 0

Bravo AF: 0.000552

EpiCase AF: 0.000436

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.6
DANN	Benign	0.45
PhyloP100		-0.068
Mutation Taster		=100/0	polymorphism

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: rs200884153; hg19: chr5-147498011; COSMIC: COSV56263490;