19-38251388-C-G

Variant names:

• chr19-38251388-C-G
• rs201166412
• NM_033256.3:c.374G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033256.3(PPP1R14A):​c.374G>C​(p.Arg125Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R125L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000056 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PPP1R14A NM_033256.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.99
• Publications: 0 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, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.014341652).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033256.3. 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
	PPP1R14A	NM_033256.3	MANE Select	c.374G>C	p.Arg125Pro	missense	Exon 4 of 4	NP_150281.1	Q96A00-1
	PPP1R14A	NM_001243947.2		c.293G>C	p.Arg98Pro	missense	Exon 3 of 3	NP_001230876.1	Q96A00-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP1R14A	ENST00000301242.9	TSL:1 MANE Select	c.374G>C	p.Arg125Pro	missense	Exon 4 of 4	ENSP00000301242.3	Q96A00-1
	PPP1R14A	ENST00000347262.8	TSL:1	c.293G>C	p.Arg98Pro	missense	Exon 3 of 3	ENSP00000301243.3	Q96A00-2
	PPP1R14A	ENST00000956130.1		c.362G>C	p.Arg121Pro	missense	Exon 4 of 4	ENSP00000626189.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.000487 AC: 88 AN: 180632 AF XY: 0.000382

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.0000910

Gnomad ASJ exome AF: 0.000255

Gnomad EAS exome AF: 0.000596

Gnomad FIN exome AF: 0.000279

Gnomad NFE exome AF: 0.000410

Gnomad OTH exome AF: 0.000720

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000564 AC: 79 AN: 1401304 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 47 AN XY: 697198

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29500

American (AMR) AF: 0.000186 AC: 6 AN: 32292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24268

East Asian (EAS) AF: 0.000342 AC: 12 AN: 35040

South Asian (SAS) AF: 0.00 AC: 0 AN: 78748

European-Finnish (FIN) AF: 0.000942 AC: 44 AN: 46716

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5492

European-Non Finnish (NFE) AF: 0.0000128 AC: 14 AN: 1091392

Other (OTH) AF: 0.0000519 AC: 3 AN: 57856

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.000745 AC: 90

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.5
DANN	Benign	0.79
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N
PhyloP100		-3.0
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.015
Sift	Benign	0.24	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.15
MVP		0.10
MPC		0.0043
ClinPred		0.0033	T
GERP RS		-6.4
Varity_R		0.23
gMVP		0.12
Mutation Taster		=84/16	polymorphism

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: rs201166412; hg19: chr19-38742028;