16-2036451-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_001130012.3(NHERF2):c.542C>T(p.Pro181Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000661 in 1,603,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: NHERF2 NM_001130012.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.878

Genes affected

NHERF2 (HGNC:11076): (NHERF family PDZ scaffold protein 2) This gene encodes a member of the NHERF family of PDZ scaffolding proteins. These proteins mediate many cellular processes by binding to and regulating the membrane expression and protein-protein interactions of membrane receptors and transport proteins. The encoded protein plays a role in intestinal sodium absorption by regulating the activity of the sodium/hydrogen exchanger 3, and may also regulate the cystic fibrosis transmembrane regulator (CFTR) ion channel. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12907866).
• BP6: Variant 16-2036451-C-T is Benign according to our data. Variant chr16-2036451-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2454425.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHERF2	NM_001130012.3	c.542C>T	p.Pro181Leu	missense_variant	3/7	ENST00000424542.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHERF2	ENST00000424542.7	c.542C>T	p.Pro181Leu	missense_variant	3/7	1	NM_001130012.3	P1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000920 AC: 21 AN: 228312 Hom.: 0 AF XY: 0.0000801 AC XY: 10 AN XY: 124810

Gnomad AFR exome AF: 0.000230

Gnomad AMR exome AF: 0.0000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000119

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000137

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000558 AC: 81 AN: 1451560 Hom.: 0 Cov.: 32 AF XY: 0.0000527 AC XY: 38 AN XY: 721308

Gnomad4 AFR exome AF: 0.000241

Gnomad4 AMR exome AF: 0.0000458

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000768

Gnomad4 SAS exome AF: 0.0000236

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000551

Gnomad4 OTH exome AF: 0.0000834

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74494

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.000128

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000239 AC: 2

ExAC AF: 0.0000830 AC: 10

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	17
Dann	Benign	0.92
DEOGEN2	Benign	0.24	T;.;.;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.2	M;M;.;.;.
MutationTaster	Benign	0.93	D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-6.1	D;D;D;D;D
REVEL	Benign	0.16
Sift	Benign	0.069	T;T;T;T;T
Sift4G	Uncertain	0.036	D;D;D;D;D
Polyphen		0.13	B;.;.;.;.
Vest4		0.22
MVP		0.35
MPC		0.070
ClinPred		0.085	T
GERP RS		2.4
Varity_R		0.50
gMVP		0.40

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

Publications

LitVar

Other links and lift over

dbSNP: rs374997543; hg19: chr16-2086452;