dbSNP rs121908404: SPINT2:p.Met1? (chr19-38264893-A-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_021102.4(SPINT2):c.1A>C(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,381,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SPINT2
NM_021102.4 initiator_codon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.37

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 3 pathogenic variants. Next in-frame start position is after 51 codons. Genomic position: 38283671. Lost 0.199 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINT2	NM_021102.4 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 7	ENST00000301244.12	NP_066925.1
SPINT2	NM_001166103.2 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 6		NP_001159575.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINT2	ENST00000301244.12 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 7	1	NM_021102.4	ENSP00000301244.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1381980

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

681982

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31436

American (AMR)

AF:

0.00

AC:

AN:

35620

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25104

East Asian (EAS)

AF:

0.00

AC:

AN:

35678

South Asian (SAS)

AF:

0.00

AC:

AN:

79064

European-Finnish (FIN)

AF:

0.0000564

AC:

AN:

35474

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1077676

Other (OTH)

AF:

0.00

AC:

AN:

57636

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.25

T;.;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.0

.;.;.

PhyloP100

1.4

PROVEAN

Benign

-0.92

N;N;.

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;D

Vest4

0.94

ClinPred

0.99

GERP RS

3.6

PromoterAI

-0.33

Neutral

(source)

Varity_R

0.92

gMVP

0.81

Mutation Taster

=4/196

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over