rs34966234

Variant names:

• chr5-148127010-G-A
• rs34966234
• NM_006846.4:c.2895G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-148127010-G-A
• chr5-148127010-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006846.4(SPINK5):​c.2895G>A​(p.Lys965Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,613,540 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (17 hom.)
• Consequence: SPINK5 NM_006846.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.268
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 5-148127010-G-A is Benign according to our data. Variant chr5-148127010-G-A is described in ClinVar as Benign. ClinVar VariationId is 351539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.268 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00697 (1061/152262) while in subpopulation AFR AF = 0.0232 (964/41540). AF 95% confidence interval is 0.022. There are 11 homozygotes in GnomAd4. There are 467 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

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.2895G>A	p.Lys965Lys	synonymous	Exon 30 of 33	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.2985G>A	p.Lys995Lys	synonymous	Exon 31 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.2895G>A	p.Lys965Lys	synonymous	Exon 30 of 33	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.2985G>A	p.Lys995Lys	synonymous	Exon 31 of 34	ENSP00000352936.3	Q9NQ38-3
	FBXO38-DT	ENST00000667608.1		n.1257-33268C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00697 AC: 1061 AN: 152144 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0233

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00171 AC: 425 AN: 248854 AF XY: 0.00135

Gnomad AFR exome AF: 0.0235

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000658 AC: 962 AN: 1461278 Hom.: 17 Cov.: 30 AF XY: 0.000608 AC XY: 442 AN XY: 726892

African (AFR) AF: 0.0226 AC: 754 AN: 33424

American (AMR) AF: 0.00166 AC: 74 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.0000405 AC: 45 AN: 1111742

Other (OTH) AF: 0.00136 AC: 82 AN: 60378

GnomAD4 genome AF: 0.00697 AC: 1061 AN: 152262 Hom.: 11 Cov.: 32 AF XY: 0.00627 AC XY: 467 AN XY: 74456

African (AFR) AF: 0.0232 AC: 964 AN: 41540

American (AMR) AF: 0.00484 AC: 74 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68018

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00327 Hom.: 2

Bravo AF: 0.00796

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.1
DANN	Benign	0.43
PhyloP100		0.27
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34966234; hg19: chr5-147506573;