rs17850241

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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]

ENSG00000267748 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 1169721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38291845-G-C is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4061 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINT2	NM_021102.4	c.598G>C	p.Val200Leu	missense_variant	7/7	ENST00000301244.12	NP_066925.1
SPINT2	NM_001166103.2	c.427G>C	p.Val143Leu	missense_variant	6/6		NP_001159575.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINT2	ENST00000301244.12	c.598G>C	p.Val200Leu	missense_variant	7/7	1	NM_021102.4	ENSP00000301244.5
ENSG00000267748	ENST00000591889.2	c.223+1270G>C		intron_variant		2		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

GnomAD3 exomes AF: 0.0286 AC: 7141 AN: 249690 Hom.: 180 AF XY: 0.0287 AC XY: 3873 AN XY: 135162

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 SAS exome AF: 0.0116

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

Gnomad4 AFR exome AF: 0.00485

Gnomad4 AMR exome AF: 0.0203

Gnomad4 ASJ exome AF: 0.0212

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0119

Gnomad4 FIN exome AF: 0.0733

Gnomad4 NFE exome AF: 0.0385

Gnomad4 OTH exome AF: 0.0308

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

Gnomad4 AFR AF: 0.00554

Gnomad4 AMR AF: 0.0266

Gnomad4 ASJ AF: 0.0184

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0129

Gnomad4 FIN AF: 0.0851

Gnomad4 NFE AF: 0.0342

Gnomad4 OTH AF: 0.0180

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

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;T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.66	T;T;T
MetaRNN	Benign	0.0021	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.4	N;.;N
REVEL	Benign	0.065
Sift	Benign	0.031	D;.;D
Sift4G	Uncertain	0.048	D;T;T
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs11548457; hg19: chr19-38782485; COSMIC: COSV56647755; COSMIC: COSV56647755;