rs6892205

Variant names:

• chr5-148095823-A-G
• rs6892205
• NM_006846.4:c.800A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-148095823-A-G
• chr5-148095823-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006846.4(SPINK5):​c.800A>G​(p.Gln267Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.514 in 1,607,930 control chromosomes in the GnomAD database, including 215,197 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q267K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.51 (19668 hom., cov: 31)
  • Exomes 𝑓: 0.52 (195529 hom.)
• Consequence: SPINK5 NM_006846.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -3.98
• Publications: 45 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.1259713E-6).
• BP6: Variant 5-148095823-A-G is Benign according to our data. Variant chr5-148095823-A-G is described in ClinVar as Benign. ClinVar VariationId is 139256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.595 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.800A>G	p.Gln267Arg	missense	Exon 10 of 33	NP_006837.2
	SPINK5	NM_001127698.2		c.800A>G	p.Gln267Arg	missense	Exon 10 of 34	NP_001121170.1
	SPINK5	NM_001127699.2		c.800A>G	p.Gln267Arg	missense	Exon 10 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.800A>G	p.Gln267Arg	missense	Exon 10 of 33	ENSP00000256084.7
	SPINK5	ENST00000359874.7	TSL:1	c.800A>G	p.Gln267Arg	missense	Exon 10 of 34	ENSP00000352936.3
	SPINK5	ENST00000398454.5	TSL:1	c.800A>G	p.Gln267Arg	missense	Exon 10 of 28	ENSP00000381472.1

Frequencies

GnomAD3 genomes AF: 0.507 AC: 76829 AN: 151480 Hom.: 19656 Cov.: 31

Gnomad AFR AF: 0.458

Gnomad AMI AF: 0.507

Gnomad AMR AF: 0.605

Gnomad ASJ AF: 0.449

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.489

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.521

GnomAD2 exomes AF: 0.532 AC: 132330 AN: 248824 AF XY: 0.526

Gnomad AFR exome AF: 0.459

Gnomad AMR exome AF: 0.709

Gnomad ASJ exome AF: 0.457

Gnomad EAS exome AF: 0.478

Gnomad FIN exome AF: 0.546

Gnomad NFE exome AF: 0.513

Gnomad OTH exome AF: 0.527

GnomAD4 exome AF: 0.515 AC: 750408 AN: 1456332 Hom.: 195529 Cov.: 35 AF XY: 0.513 AC XY: 372040 AN XY: 724698

African (AFR) AF: 0.454 AC: 15097 AN: 33282

American (AMR) AF: 0.695 AC: 30945 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 11878 AN: 26028

East Asian (EAS) AF: 0.451 AC: 17850 AN: 39610

South Asian (SAS) AF: 0.487 AC: 41938 AN: 86146

European-Finnish (FIN) AF: 0.545 AC: 29052 AN: 53324

Middle Eastern (MID) AF: 0.519 AC: 2965 AN: 5712

European-Non Finnish (NFE) AF: 0.515 AC: 569918 AN: 1107590

Other (OTH) AF: 0.512 AC: 30765 AN: 60084

GnomAD4 genome AF: 0.507 AC: 76871 AN: 151598 Hom.: 19668 Cov.: 31 AF XY: 0.510 AC XY: 37743 AN XY: 74066

African (AFR) AF: 0.458 AC: 18930 AN: 41376

American (AMR) AF: 0.605 AC: 9192 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.449 AC: 1558 AN: 3468

East Asian (EAS) AF: 0.475 AC: 2424 AN: 5106

South Asian (SAS) AF: 0.491 AC: 2360 AN: 4810

European-Finnish (FIN) AF: 0.533 AC: 5601 AN: 10518

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.518 AC: 35101 AN: 67824

Other (OTH) AF: 0.521 AC: 1098 AN: 2108

Alfa AF: 0.513 Hom.: 77598

Bravo AF: 0.514

TwinsUK AF: 0.526 AC: 1952

ALSPAC AF: 0.521 AC: 2008

ESP6500AA AF: 0.460 AC: 1667

ESP6500EA AF: 0.508 AC: 4132

ExAC AF: 0.521 AC: 62900

Asia WGS AF: 0.533 AC: 1846 AN: 3476

EpiCase AF: 0.514

EpiControl AF: 0.524

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)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.0010
DANN	Benign	0.12
DEOGEN2	Benign	0.027	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0010	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.0000051	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.59	N
PhyloP100		-4.0
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.047
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.019
MPC		0.10
ClinPred		0.0035	T
GERP RS		-7.6
Varity_R		0.051
gMVP		0.23
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: rs6892205; hg19: chr5-147475386; COSMIC: COSV56248822;