16-2027059-G-T

Position:

chr16-2027059-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000424542.7(NHERF2):c.54G>T(p.Glu18Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000012 in 1,413,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

NHERF2
ENST00000424542.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.825

Variant links:

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]

NHERF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013304144).

BS2

High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NHERF2	NM_001130012.3 linkuse as main transcript	c.54G>T	p.Glu18Asp	missense_variant	1/7	ENST00000424542.7	NP_001123484.1
NHERF2	NM_004785.6 linkuse as main transcript	c.54G>T	p.Glu18Asp	missense_variant	1/7		NP_004776.3
NHERF2	XM_047434923.1 linkuse as main transcript	c.54G>T	p.Glu18Asp	missense_variant	1/7		XP_047290879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NHERF2	ENST00000424542.7 linkuse as main transcript	c.54G>T	p.Glu18Asp	missense_variant	1/7	1	NM_001130012.3	ENSP00000408005	P1	Q15599-1
NHERF2	ENST00000432365.6 linkuse as main transcript	c.54G>T	p.Glu18Asp	missense_variant	1/7	1		ENSP00000402857		Q15599-2
NHERF2	ENST00000567504.5 linkuse as main transcript	c.186+1393G>T		intron_variant		3		ENSP00000454361

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000823

AC:

AN:

72930

Hom.:

AF XY:

0.0000237

AC XY:

AN XY:

42250

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00257

Gnomad SAS 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:

0.0000111

AC:

AN:

1262074

Hom.:

Cov.:

AF XY:

0.0000145

AC XY:

AN XY:

620752

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000493

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000195

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151362

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73982

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000581

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000642

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2023

The c.54G>T (p.E18D) alteration is located in exon 1 (coding exon 1) of the SLC9A3R2 gene. This alteration results from a G to T substitution at nucleotide position 54, causing the glutamic acid (E) at amino acid position 18 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.63

DEOGEN2

Benign

0.030

T;.

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.85

T;T

M_CAP

Benign

0.062

MetaRNN

Benign

0.013

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.46

N;N

MutationTaster

Benign

0.85

N;N

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.24

N;N

REVEL

Benign

0.023

Sift

Benign

0.56

T;T

Sift4G

Benign

0.76

T;T

Polyphen

0.040

B;.

Vest4

0.045

MutPred

0.37

Loss of disorder (P = 0.0887);Loss of disorder (P = 0.0887);

MVP

0.40

MPC

0.046

ClinPred

0.012

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.21

gMVP

0.21

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over