rs121908404

Positions:

• chr19-38264893-A-G
• chr19-38264893-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The ENST00000301244.12(SPINT2):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,381,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: SPINT2 ENST00000301244.12 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.37

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in ENST00000301244.12 (SPINT2) was described as [Pathogenic] in ClinVar as 5208
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINT2	NM_021102.4	c.1A>G	p.Met1?	start_lost	1/7	ENST00000301244.12	NP_066925.1
SPINT2	NM_001166103.2	c.1A>G	p.Met1?	start_lost	1/6		NP_001159575.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINT2	ENST00000301244.12	c.1A>G	p.Met1?	start_lost	1/7	1	NM_021102.4	ENSP00000301244	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1381980 Hom.: 0 Cov.: 31 AF XY: 0.00000440 AC XY: 3 AN XY: 681982

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.28	T;.;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-0.75	N;N;.
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.062	B;.;.
Vest4		0.89
MutPred		0.99		Gain of catalytic residue at M1 (P = 0.025);Gain of catalytic residue at M1 (P = 0.025);Gain of catalytic residue at M1 (P = 0.025);
MVP		0.64
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.91
gMVP		0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908404; hg19: chr19-38755533;