Genetic Variant SPINT2:c.-44-19279G>A (chr19-38264348-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The ENST00000590510.5(SPINT2):c.-44-19279G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 152,190 control chromosomes in the GnomAD database, including 4,262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.23 ( 4251 hom., cov: 32)

Exomes 𝑓: 0.29 ( 11 hom. )

Consequence

SPINT2
ENST00000590510.5 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.92

Publications

4 publications found

Variant links:

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

SPINT2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 19-38264348-G-A is Benign according to our data. Variant chr19-38264348-G-A is described in ClinVar as Benign. ClinVar VariationId is 1276397.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000590510.5. 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.-545G>A		upstream_gene	N/A	NP_066925.1	O43291-1
	SPINT2	NM_001166103.2		c.-545G>A		upstream_gene	N/A	NP_001159575.1	O43291-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SPINT2	ENST00000590510.5	TSL:3	c.-44-19279G>A	intron	N/A	ENSP00000465301.1	K7EJS4
SPINT2	ENST00000301244.12	TSL:1 MANE Select	c.-545G>A	upstream_gene	N/A	ENSP00000301244.5	O43291-1
SPINT2	ENST00000454580.7	TSL:1	c.-545G>A	upstream_gene	N/A	ENSP00000389788.2	O43291-2

Frequencies

GnomAD3 genomes

AF:

0.233

AC:

35408

AN:

151864

Hom.:

4230

Cov.:

show subpopulations

Gnomad AFR

AF:

0.214

Gnomad AMI

AF:

0.148

Gnomad AMR

AF:

0.283

Gnomad ASJ

AF:

0.198

Gnomad EAS

AF:

0.280

Gnomad SAS

AF:

0.218

Gnomad FIN

AF:

0.216

Gnomad MID

AF:

0.143

Gnomad NFE

AF:

0.238

Gnomad OTH

AF:

0.220

GnomAD4 exome

AF:

0.287

AC:

AN:

216

Hom.:

AF XY:

0.281

AC XY:

AN XY:

160

show subpopulations

African (AFR)

AF:

0.250

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.500

AC:

AN:

South Asian (SAS)

AF:

0.250

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.285

AC:

AN:

172

Other (OTH)

AF:

0.125

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.233

AC:

35474

AN:

151974

Hom.:

4251

Cov.:

AF XY:

0.235

AC XY:

17443

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.214

AC:

8873

AN:

41494

American (AMR)

AF:

0.285

AC:

4348

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.198

AC:

685

AN:

3466

East Asian (EAS)

AF:

0.280

AC:

1433

AN:

5116

South Asian (SAS)

AF:

0.219

AC:

1055

AN:

4824

European-Finnish (FIN)

AF:

0.216

AC:

2291

AN:

10584

Middle Eastern (MID)

AF:

0.147

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.238

AC:

16150

AN:

67902

Other (OTH)

AF:

0.218

AC:

461

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1392

2784

4176

5568

6960

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

372

744

1116

1488

1860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.228

Hom.:

626

Bravo

AF:

0.242

Asia WGS

AF:

0.249

AC:

864

AN:

3468

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.15

(source)

DANN

Benign

0.74

PhyloP100

-3.9

PromoterAI

-0.020

Neutral

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over