NM_033256.3:c.109G>C

Variant names:

• chr19-38256231-C-G
• rs1166839796
• NM_033256.3:c.109G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_033256.3(PPP1R14A):​c.109G>C​(p.Val37Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000357 in 1,400,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. V37I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: PPP1R14A NM_033256.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.17
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.289764).

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.109G>C	p.Val37Leu	missense	Exon 1 of 4	NP_150281.1	Q96A00-1
	PPP1R14A	NM_001243947.2		c.109G>C	p.Val37Leu	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.109G>C	p.Val37Leu	missense	Exon 1 of 4	ENSP00000301242.3	Q96A00-1
	PPP1R14A	ENST00000347262.8	TSL:1	c.109G>C	p.Val37Leu	missense	Exon 1 of 3	ENSP00000301243.3	Q96A00-2
	PPP1R14A	ENST00000956130.1		c.109G>C	p.Val37Leu	missense	Exon 1 of 4	ENSP00000626189.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000652 AC: 1 AN: 153342 AF XY: 0.0000120

Gnomad AFR exome AF: 0.000117

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000357 AC: 5 AN: 1400350 Hom.: 0 Cov.: 31 AF XY: 0.00000289 AC XY: 2 AN XY: 692294

African (AFR) AF: 0.000155 AC: 5 AN: 32290

American (AMR) AF: 0.00 AC: 0 AN: 37280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25194

East Asian (EAS) AF: 0.00 AC: 0 AN: 36700

South Asian (SAS) AF: 0.00 AC: 0 AN: 79864

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39770

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5448

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085482

Other (OTH) AF: 0.00 AC: 0 AN: 58322

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Benign	0.038	T
Eigen	Benign	0.10
Eigen_PC	Benign	0.064
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.2
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.46
Sift	Benign	0.38	T
Sift4G	Benign	0.088	T
Polyphen		0.98	D
Vest4		0.46
MutPred		0.74		Loss of methylation at K40 (P = 0.0665)
MVP		0.085
MPC		2.7
ClinPred		0.42	T
GERP RS		3.4
PromoterAI		-0.20	Neutral
Varity_R		0.26
gMVP		0.75
Mutation Taster		=66/34	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: rs1166839796; hg19: chr19-38746871;