19-38256281-G-A

Variant names:

• chr19-38256281-G-A
• rs1168277269
• NM_033256.3:c.59C>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.59C>T​(p.Ala20Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000072 in 1,388,660 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: PPP1R14A NM_033256.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.14
• 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=0.24863574).

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.59C>T	p.Ala20Val	missense	Exon 1 of 4	NP_150281.1	Q96A00-1
	PPP1R14A	NM_001243947.2		c.59C>T	p.Ala20Val	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.59C>T	p.Ala20Val	missense	Exon 1 of 4	ENSP00000301242.3	Q96A00-1
	PPP1R14A	ENST00000347262.8	TSL:1	c.59C>T	p.Ala20Val	missense	Exon 1 of 3	ENSP00000301243.3	Q96A00-2
	PPP1R14A	ENST00000956130.1		c.59C>T	p.Ala20Val	missense	Exon 1 of 4	ENSP00000626189.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.20e-7 AC: 1 AN: 1388660 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 685886

African (AFR) AF: 0.00 AC: 0 AN: 31774

American (AMR) AF: 0.00 AC: 0 AN: 36202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25086

East Asian (EAS) AF: 0.0000276 AC: 1 AN: 36252

South Asian (SAS) AF: 0.00 AC: 0 AN: 79450

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4696

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081540

Other (OTH) AF: 0.00 AC: 0 AN: 57904

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T
Eigen	Benign	0.059
Eigen_PC	Benign	0.0066
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.1
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.041
Sift	Benign	0.079	T
Sift4G	Benign	0.20	T
Polyphen		0.94	P
Vest4		0.14
MutPred		0.41		Loss of glycosylation at P17 (P = 0.1007)
MVP		0.12
MPC		2.5
ClinPred		0.73	D
GERP RS		3.3
PromoterAI		-0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.40
Mutation Taster		=88/12	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: rs1168277269; hg19: chr19-38746921;