chr19-38290215-A-G

Variant names:

• chr19-38290215-A-G
• rs121908403
• NM_021102.4:c.488A>G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS3 PP3_Moderate PP5_Very_Strong BS1_Supporting

The NM_021102.4(SPINT2):​c.488A>G​(p.Tyr163Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000197 in 1,612,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002209585: Experimental studies have shown that this missense change affects SPINT2 function (PMID:19185281, 30445423).; SCV004801459: Heinz-Erian et al. (2009) demonstrated a significant decrease in the ability of the p.Tyr163Cys variant protein to inhibit trypsin as compared to wild type when transiently transfected in COS7 cells, and studies in Xenopus oocytes by Faller et al. (2014) showed a complete loss of inhibitory activity by the p.Tyr163Cys variant protein on two proteases, which may ultimately lead to excessive proteolytic activity.".

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: SPINT2 NM_021102.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.39
• Publications: 20 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, Labcorp Genetics (formerly Invitae), PanelApp Australia

ENSG00000267748 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002209585: Experimental studies have shown that this missense change affects SPINT2 function (PMID: 19185281, 30445423).; SCV004801459: Heinz-Erian et al. (2009) demonstrated a significant decrease in the ability of the p.Tyr163Cys variant protein to inhibit trypsin as compared to wild type when transiently transfected in COS7 cells, and studies in Xenopus oocytes by Faller et al. (2014) showed a complete loss of inhibitory activity by the p.Tyr163Cys variant protein on two proteases, which may ultimately lead to excessive proteolytic activity.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874
• PP5: Variant 19-38290215-A-G is Pathogenic according to our data. Variant chr19-38290215-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 5205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000203 (296/1460170) while in subpopulation NFE AF = 0.000254 (282/1112002). AF 95% confidence interval is 0.000229. There are 0 homozygotes in GnomAdExome4. There are 139 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.488A>G	p.Tyr163Cys	missense	Exon 5 of 7	NP_066925.1	O43291-1
	SPINT2	NM_001166103.2		c.317A>G	p.Tyr106Cys	missense	Exon 4 of 6	NP_001159575.1	O43291-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINT2	ENST00000301244.12	TSL:1 MANE Select	c.488A>G	p.Tyr163Cys	missense	Exon 5 of 7	ENSP00000301244.5	O43291-1
	SPINT2	ENST00000454580.7	TSL:1	c.317A>G	p.Tyr106Cys	missense	Exon 4 of 6	ENSP00000389788.2	O43291-2
	ENSG00000267748	ENST00000591889.2	TSL:2	c.119A>G	p.Tyr40Cys	missense	Exon 2 of 6	ENSP00000468040.1	K7EQZ3

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000207 AC: 52 AN: 251384 AF XY: 0.000191

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000431

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000203 AC: 296 AN: 1460170 Hom.: 0 Cov.: 31 AF XY: 0.000191 AC XY: 139 AN XY: 726394

African (AFR) AF: 0.0000598 AC: 2 AN: 33426

American (AMR) AF: 0.0000447 AC: 2 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86178

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4360

European-Non Finnish (NFE) AF: 0.000254 AC: 282 AN: 1112002

Other (OTH) AF: 0.000133 AC: 8 AN: 60234

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74350

African (AFR) AF: 0.0000241 AC: 1 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68036

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000280 Hom.: 0

Bravo AF: 0.000121

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000305 AC: 37

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Congenital secretory sodium diarrhea 3 (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		4.4
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-8.7	D
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.94
MPC		1.3
ClinPred		1.0	D
GERP RS		4.5
PromoterAI		-0.0085	Neutral
Varity_R		0.89
gMVP		0.99
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121908403; hg19: chr19-38780855;