19-38256164-C-A

Variant names:

• chr19-38256164-C-A
• rs781410125
• NM_033256.3:c.176G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033256.3(PPP1R14A):​c.176G>T​(p.Arg59Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,396,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. R59H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PPP1R14A NM_033256.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.18
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22576016).

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.176G>T	p.Arg59Leu	missense	Exon 1 of 4	NP_150281.1	Q96A00-1
	PPP1R14A	NM_001243947.2		c.176G>T	p.Arg59Leu	missense	Exon 1 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.176G>T	p.Arg59Leu	missense	Exon 1 of 4	ENSP00000301242.3	Q96A00-1
	PPP1R14A	ENST00000347262.8	TSL:1	c.176G>T	p.Arg59Leu	missense	Exon 1 of 3	ENSP00000301243.3	Q96A00-2
	PPP1R14A	ENST00000956130.1		c.176G>T	p.Arg59Leu	missense	Exon 1 of 4	ENSP00000626189.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000671 AC: 1 AN: 148994 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000168

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1396362 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690092

African (AFR) AF: 0.00 AC: 0 AN: 31942

American (AMR) AF: 0.00 AC: 0 AN: 36654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25188

East Asian (EAS) AF: 0.00 AC: 0 AN: 36332

South Asian (SAS) AF: 0.00 AC: 0 AN: 79744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39042

Middle Eastern (MID) AF: 0.000182 AC: 1 AN: 5480

European-Non Finnish (NFE) AF: 9.23e-7 AC: 1 AN: 1083824

Other (OTH) AF: 0.0000172 AC: 1 AN: 58156

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.2
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.10
Sift	Benign	0.086	T
Sift4G	Uncertain	0.048	D
Polyphen		0.081	B
Vest4		0.40
MutPred		0.62		Loss of MoRF binding (P = 0.0341)
MVP		0.099
MPC		2.1
ClinPred		0.85	D
GERP RS		4.0
PromoterAI		-0.0078	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.26
gMVP		0.57
Mutation Taster		=86/14	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: rs781410125; hg19: chr19-38746804;