rs11548457

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021102.4(SPINT2):c.598G>C(p.Val200Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0343 in 1,612,424 control chromosomes in the GnomAD database, including 1,203 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 (★★).

Frequency

Genomes: 𝑓 0.027 ( 110 hom., cov: 33)

Exomes 𝑓: 0.035 ( 1093 hom. )

Consequence

SPINT2
NM_021102.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.66

Publications

17 publications found

Variant links:

Genes affected

SPINT2 (HGNC:11247): (serine peptidase inhibitor, Kunitz type 2) This gene encodes a transmembrane protein with two extracellular Kunitz domains that inhibits a variety of serine proteases. The protein inhibits HGF activator which prevents the formation of active hepatocyte growth factor. This gene is a putative tumor suppressor, and mutations in this gene result in congenital sodium diarrhea. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

SPINT2 Gene-Disease associations (from GenCC):

syndromic congenital sodium diarrhea
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
congenital secretory sodium diarrhea 3
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)

SPINT2 links:

ENSG00000267748 (HGNC:):

ENSG00000267748 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020741224).

BP6

Variant 19-38291845-G-C is Benign according to our data. Variant chr19-38291845-G-C is described in ClinVar as Benign. ClinVar VariationId is 1169721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0267 (4061/152246) while in subpopulation NFE AF = 0.0342 (2328/68026). AF 95% confidence interval is 0.0331. There are 110 homozygotes in GnomAd4. There are 2114 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 110 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINT2	NM_021102.4 link	c.598G>C	p.Val200Leu	missense_variant	Exon 7 of 7	ENST00000301244.12	NP_066925.1
SPINT2	NM_001166103.2 link	c.427G>C	p.Val143Leu	missense_variant	Exon 6 of 6		NP_001159575.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINT2	ENST00000301244.12 link	c.598G>C	p.Val200Leu	missense_variant	Exon 7 of 7	1	NM_021102.4	ENSP00000301244.5
ENSG00000267748	ENST00000591889.2 link	c.223+1270G>C		intron_variant	Intron 3 of 5	2		ENSP00000468040.1

Frequencies

GnomAD3 genomes

AF:

0.0267

AC:

4062

AN:

152128

Hom.:

110

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00555

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.0267

Gnomad ASJ

AF:

0.0184

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0129

Gnomad FIN

AF:

0.0851

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0342

Gnomad OTH

AF:

0.0182

GnomAD2 exomes

AF:

0.0286

AC:

7141

AN:

249690

AF XY:

0.0287

show subpopulations

Gnomad AFR exome

AF:

0.00420

Gnomad AMR exome

AF:

0.0201

Gnomad ASJ exome

AF:

0.0226

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0787

Gnomad NFE exome

AF:

0.0351

Gnomad OTH exome

AF:

0.0282

GnomAD4 exome

AF:

0.0351

AC:

51309

AN:

1460178

Hom.:

1093

Cov.:

AF XY:

0.0343

AC XY:

24941

AN XY:

726384

show subpopulations

African (AFR)

AF:

0.00485

AC:

162

AN:

33430

American (AMR)

AF:

0.0203

AC:

909

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.0212

AC:

553

AN:

26128

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.0119

AC:

1022

AN:

86160

European-Finnish (FIN)

AF:

0.0733

AC:

3916

AN:

53394

Middle Eastern (MID)

AF:

0.0226

AC:

104

AN:

4608

European-Non Finnish (NFE)

AF:

0.0385

AC:

42788

AN:

1111832

Other (OTH)

AF:

0.0308

AC:

1853

AN:

60228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

2767

5534

8300

11067

13834

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1642

3284

4926

6568

8210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0267

AC:

4061

AN:

152246

Hom.:

110

Cov.:

AF XY:

0.0284

AC XY:

2114

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00554

AC:

230

AN:

41552

American (AMR)

AF:

0.0266

AC:

407

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0184

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.0129

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0851

AC:

902

AN:

10600

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0342

AC:

2328

AN:

68026

Other (OTH)

AF:

0.0180

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

209

418

627

836

1045

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0282

Hom.:

Bravo

AF:

0.0227

TwinsUK

AF:

0.0361

AC:

134

ALSPAC

AF:

0.0454

AC:

175

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.0344

AC:

296

ExAC

AF:

0.0278

AC:

3373

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.0315

EpiControl

AF:

0.0336

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.32

T;T;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.66

T;T;T

MetaRNN

Benign

0.0021

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

M;.;.

PhyloP100

2.7

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.4

N;.;N

REVEL

Benign

0.065

Sift

Benign

0.031

D;.;D

Sift4G

Uncertain

0.048

D;T;T

Polyphen

0.28

B;.;.

Vest4

0.13

MPC

0.48

ClinPred

0.024

GERP RS

3.7

Varity_R

0.062

gMVP

0.66

Mutation Taster

=86/14

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over