chr19-38264893-A-T

Variant names:

• chr19-38264893-A-T
• rs121908404
• NM_021102.4:c.1A>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PVS1_Supporting PP5 BS2_Supporting

The NM_021102.4(SPINT2):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000651 in 1,381,980 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 (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000065 (0 hom.)
• Consequence: SPINT2 NM_021102.4 initiator_codon
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• 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 Uncertain_significance. Variant got 1 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 51 codons. Genomic position: 38283671. Lost 0.199 part of the original CDS.
• PP5: Variant 19-38264893-A-T is Pathogenic according to our data. Variant chr19-38264893-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 5208.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAdExome4 at 9 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINT2	NM_021102.4	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 7	ENST00000301244.12	NP_066925.1
SPINT2	NM_001166103.2	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 6		NP_001159575.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINT2	ENST00000301244.12	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 7	1	NM_021102.4	ENSP00000301244.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000651 AC: 9 AN: 1381980 Hom.: 0 Cov.: 31 AF XY: 0.00000147 AC XY: 1 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: 0.000168

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000278

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital secretory sodium diarrhea 3 Pathogenic:1

Feb 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	21
DANN	Benign	0.83
DEOGEN2	Benign	0.25	T;.;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.72	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
PROVEAN	Benign	-0.92	N;N;.
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.028	B;.;.
Vest4		0.94
MutPred		0.99		Gain of stability (P = 0.0364);Gain of stability (P = 0.0364);Gain of stability (P = 0.0364);
MVP		0.51
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.92
gMVP		0.81

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;