rs12610267

Variant names:

• chr19-38254093-A-G
• rs12610267
• NM_033256.3:c.202-1119T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033256.3(PPP1R14A):​c.202-1119T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.468 in 152,028 control chromosomes in the GnomAD database, including 17,774 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.47 (17774 hom., cov: 32)
• Consequence: PPP1R14A NM_033256.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0800
• Publications: 25 publications found

Genes affected

PPP1R14A (HGNC:14871): (protein phosphatase 1 regulatory inhibitor subunit 14A) The protein encoded by this gene belongs to the protein phosphatase 1 (PP1) inhibitor family. This protein is an inhibitor of smooth muscle myosin phosphatase, and has higher inhibitory activity when phosphorylated. Inhibition of myosin phosphatase leads to increased myosin phosphorylation and enhanced smooth muscle contraction. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Sep 2011]

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, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.713 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1R14A	NM_033256.3	c.202-1119T>C		intron_variant	Intron 1 of 3	ENST00000301242.9	NP_150281.1
PPP1R14A	NM_001243947.2	c.202-1755T>C		intron_variant	Intron 1 of 2		NP_001230876.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1R14A	ENST00000301242.9	c.202-1119T>C		intron_variant	Intron 1 of 3	1	NM_033256.3	ENSP00000301242.3

Frequencies

GnomAD3 genomes AF: 0.468 AC: 71100 AN: 151910 Hom.: 17744 Cov.: 32

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.529

Gnomad ASJ AF: 0.434

Gnomad EAS AF: 0.734

Gnomad SAS AF: 0.602

Gnomad FIN AF: 0.622

Gnomad MID AF: 0.360

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.435

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.468 AC: 71195 AN: 152028 Hom.: 17774 Cov.: 32 AF XY: 0.480 AC XY: 35638 AN XY: 74312

African (AFR) AF: 0.320 AC: 13278 AN: 41458

American (AMR) AF: 0.530 AC: 8100 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.434 AC: 1503 AN: 3464

East Asian (EAS) AF: 0.733 AC: 3777 AN: 5154

South Asian (SAS) AF: 0.602 AC: 2904 AN: 4820

European-Finnish (FIN) AF: 0.622 AC: 6579 AN: 10584

Middle Eastern (MID) AF: 0.349 AC: 102 AN: 292

European-Non Finnish (NFE) AF: 0.497 AC: 33762 AN: 67952

Other (OTH) AF: 0.439 AC: 928 AN: 2114

Alfa AF: 0.479 Hom.: 35321

Bravo AF: 0.456

Asia WGS AF: 0.653 AC: 2267 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.9
DANN	Benign	0.34
PhyloP100		0.080
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12610267; hg19: chr19-38744733;