rs17850241

Variant names:

• chr19-38291845-G-T
• rs11548457
• NM_021102.4:c.598G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-38291845-G-T
• chr19-38291845-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021102.4(SPINT2):​c.598G>T​(p.Val200Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V200L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SPINT2 NM_021102.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.66
• Publications: 17 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: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ENSG00000267748 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2917561).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINT2	NM_021102.4	c.598G>T	p.Val200Phe	missense_variant	Exon 7 of 7	ENST00000301244.12	NP_066925.1
SPINT2	NM_001166103.2	c.427G>T	p.Val143Phe	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	c.598G>T	p.Val200Phe	missense_variant	Exon 7 of 7	1	NM_021102.4	ENSP00000301244.5
ENSG00000267748	ENST00000591889.2	c.223+1270G>T		intron_variant	Intron 3 of 5	2		ENSP00000468040.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460226 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726408

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4608

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111862

Other (OTH) AF: 0.00 AC: 0 AN: 60230

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 53

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T;.
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.073
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.0	M;.;.
PhyloP100		2.7
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.5	N;.;N
REVEL	Benign	0.24
Sift	Uncertain	0.0050	D;.;D
Sift4G	Uncertain	0.0080	D;D;T
Polyphen		0.14	B;.;.
Vest4		0.31
MutPred		0.38		Loss of sheet (P = 0.0817);.;.;
MVP		0.79
MPC		0.63
ClinPred		0.90	D
GERP RS		3.7
Varity_R		0.19
gMVP		0.83
Mutation Taster		=78/22	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: rs11548457; hg19: chr19-38782485;