ENST00000590510.5:c.-45+839C>T

Variant names:

• chr19-38244973-C-T
• rs8102476
• ENST00000590510.5:c.-45+839C>T

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The ENST00000590510.5(SPINT2):c.-45+839C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. Note: ENST00000590510.5 is not a MANE Select or MANE Plus Clinical transcript for SPINT2; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant allele was found at a cumulative frequency of 0.41 (AC=62,270) in the gnomAD database across 151,804 control chromosomes, including 13,965 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.627. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.41 (13965 hom., cov: 31)
• Consequence: SPINT2 ENST00000590510.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.00
• Publications: 113 publications found

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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); No splicing predictor data available.; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.6275 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: ENST00000590510.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SPINT2 ENST00000590510.5	TSL:3	c.-45+839C>T	intron	Intron 1 of 2	Prot: ENSP00000465301.1 UniProt:

SPINT2 ENST00000590510.5

TSL:3

HGVSc / HGVSpc.-45+839C>T

Exon rankIntron 1 of 2

intron

Prot: ENSP00000465301.1UniProt: K7EJS4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.410	AC:62211	Hom:13959	AN:151686	Cov:31
GnomAD4 genome	AF: 0.410	AC:62270	Hom:13965	AN:151804	Cov:31
TOPMed (Bravo)	AF: 0.392	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.433	AC:322220	Hom:72018	AN:743838	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.409	AC:957	Hom:199	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.652	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.457	AC:137	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.578	AC:2004	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.639	AC:4617	Hom:	AN:7230	Cov:
Qatari Genome	AF: 0.347	AC:61	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.623	AC:76264	Hom:23820	AN:122386	Cov:
Turkish Variome	AF: 0.466	AC:720	Hom:180	AN:1544	Cov:
UK10K	AF: 0.472	AC:3566	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.644	AC:5772	Hom:1875	AN:8960	Cov:

Showing 14 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	1.2
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.91
DANN	Benign	0.45
GPN-Star LLR	N/A	2.1
GPN-Star score	N/A	1.9
PhyloP100	Benign	-2.0

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0

Showing 1 of 1 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs8102476;

hg19: chr19-38735613;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar