19-38291845-G-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021102.4(SPINT2):​c.598G>C​(p.Val200Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0343 in 1,612,424 control chromosomes in the GnomAD database, including 1,203 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (110 hom., cov: 33)
  • Exomes 𝑓: 0.035 (1093 hom.)
• Consequence: SPINT2 NM_021102.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020741224).
• BP6: Variant 19-38291845-G-C is Benign according to our data. Variant chr19-38291845-G-C is described in ClinVar as Benign. ClinVar VariationId is 1169721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0267 (4061/152246) while in subpopulation NFE AF = 0.0342 (2328/68026). AF 95% confidence interval is 0.0331. There are 110 homozygotes in GnomAd4. There are 2114 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 110 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINT2	NM_021102.4	MANE Select	c.598G>C	p.Val200Leu	missense	Exon 7 of 7	NP_066925.1
	SPINT2	NM_001166103.2		c.427G>C	p.Val143Leu	missense	Exon 6 of 6	NP_001159575.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINT2	ENST00000301244.12	TSL:1 MANE Select	c.598G>C	p.Val200Leu	missense	Exon 7 of 7	ENSP00000301244.5
	SPINT2	ENST00000454580.7	TSL:1	c.427G>C	p.Val143Leu	missense	Exon 6 of 6	ENSP00000389788.2
	ENSG00000267748	ENST00000591889.2	TSL:2	c.223+1270G>C		intron	N/A	ENSP00000468040.1

Frequencies

GnomAD3 genomes AF: 0.0267 AC: 4062 AN: 152128 Hom.: 110 Cov.: 33

Gnomad AFR AF: 0.00555

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0267

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0129

Gnomad FIN AF: 0.0851

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0342

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0286 AC: 7141 AN: 249690 AF XY: 0.0287

Gnomad AFR exome AF: 0.00420

Gnomad AMR exome AF: 0.0201

Gnomad ASJ exome AF: 0.0226

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0787

Gnomad NFE exome AF: 0.0351

Gnomad OTH exome AF: 0.0282

GnomAD4 exome AF: 0.0351 AC: 51309 AN: 1460178 Hom.: 1093 Cov.: 31 AF XY: 0.0343 AC XY: 24941 AN XY: 726384

African (AFR) AF: 0.00485 AC: 162 AN: 33430

American (AMR) AF: 0.0203 AC: 909 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0212 AC: 553 AN: 26128

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.0119 AC: 1022 AN: 86160

European-Finnish (FIN) AF: 0.0733 AC: 3916 AN: 53394

Middle Eastern (MID) AF: 0.0226 AC: 104 AN: 4608

European-Non Finnish (NFE) AF: 0.0385 AC: 42788 AN: 1111832

Other (OTH) AF: 0.0308 AC: 1853 AN: 60228

GnomAD4 genome AF: 0.0267 AC: 4061 AN: 152246 Hom.: 110 Cov.: 33 AF XY: 0.0284 AC XY: 2114 AN XY: 74444

African (AFR) AF: 0.00554 AC: 230 AN: 41552

American (AMR) AF: 0.0266 AC: 407 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 64 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.0129 AC: 62 AN: 4820

European-Finnish (FIN) AF: 0.0851 AC: 902 AN: 10600

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0342 AC: 2328 AN: 68026

Other (OTH) AF: 0.0180 AC: 38 AN: 2114

Alfa AF: 0.0282 Hom.: 53

Bravo AF: 0.0227

TwinsUK AF: 0.0361 AC: 134

ALSPAC AF: 0.0454 AC: 175

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.0344 AC: 296

ExAC AF: 0.0278 AC: 3373

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.0315

EpiControl AF: 0.0336

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.7
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.065
Sift	Benign	0.031	D
Sift4G	Uncertain	0.048	D
Polyphen		0.28	B
Vest4		0.13
MPC		0.48
ClinPred		0.024	T
GERP RS		3.7
Varity_R		0.062
gMVP		0.66
Mutation Taster		=86/14	polymorphism (auto)

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; COSMIC: COSV56647755; COSMIC: COSV56647755;