rs121908404

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PS3 PM2 PP5_Moderate

The NM_021102.4(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. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV005700626: Studies have shown that disruption of the initiator codon alters SPINT2 gene expression (PMID:19185281).".

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: SPINT2 NM_021102.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.37
• Publications: 5 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, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 3 pathogenic variants. Next in-frame start position is after 51 codons. Genomic position: 38283671. Lost 0.199 part of the original CDS.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV005700626: Studies have shown that disruption of the initiator codon alters SPINT2 gene expression (PMID: 19185281).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-38264893-A-G is Pathogenic according to our data. Variant chr19-38264893-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 3611761.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINT2	NM_021102.4	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 7	NP_066925.1	O43291-1
	SPINT2	NM_001166103.2		c.1A>G	p.Met1?	start_lost	Exon 1 of 6	NP_001159575.1	O43291-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINT2	ENST00000301244.12	TSL:1 MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 7	ENSP00000301244.5	O43291-1
	SPINT2	ENST00000454580.7	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 1 of 6	ENSP00000389788.2	O43291-2
	SPINT2	ENST00000902579.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 7	ENSP00000572638.1

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

African (AFR) AF: 0.00 AC: 0 AN: 31436

American (AMR) AF: 0.00 AC: 0 AN: 35620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25104

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35678

South Asian (SAS) AF: 0.00 AC: 0 AN: 79064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4292

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1077676

Other (OTH) AF: 0.00 AC: 0 AN: 57636

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.81	T
PhyloP100		1.4
PROVEAN	Benign	-0.75	N
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.062	B
Vest4		0.89
MutPred		0.99		Gain of catalytic residue at M1 (P = 0.025)
MVP		0.64
ClinPred		0.99	D
GERP RS		3.6
PromoterAI		-0.32	Neutral
Varity_R		0.91
gMVP		0.86
Mutation Taster		=4/196	disease causing

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

Other links and lift over

dbSNP: rs121908404; hg19: chr19-38755533;