chr19-38290282-T-A

Variant names:

• chr19-38290282-T-A
• rs112576957
• NM_021102.4:c.553+2T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_021102.4(SPINT2):​c.553+2T>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPINT2 NM_021102.4 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.20
• Publications: 5 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: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.21343873 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-38290282-T-A is Pathogenic according to our data. Variant chr19-38290282-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 5207.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021102.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINT2	NM_021102.4	MANE Select	c.553+2T>A		splice_donor intron	N/A	NP_066925.1
	SPINT2	NM_001166103.2		c.382+2T>A		splice_donor intron	N/A	NP_001159575.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINT2	ENST00000301244.12	TSL:1 MANE Select	c.553+2T>A		splice_donor intron	N/A	ENSP00000301244.5
	SPINT2	ENST00000454580.7	TSL:1	c.382+2T>A		splice_donor intron	N/A	ENSP00000389788.2
	ENSG00000267748	ENST00000591889.2	TSL:2	c.184+2T>A		splice_donor intron	N/A	ENSP00000468040.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital secretory sodium diarrhea 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Benign	0.93
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.90	D
PhyloP100		2.2
GERP RS		4.2
PromoterAI		-0.21	Neutral
Mutation Taster		=12/87	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: -2

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

Other links and lift over

dbSNP: rs112576957; hg19: chr19-38780922;