16-2029681-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001130012.3(NHERF2):c.313G>A(p.Glu105Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000218 in 1,562,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

NHERF2
NM_001130012.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.65

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22010934).

BS2

High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NHERF2	NM_001130012.3 linkuse as main transcript	c.313G>A	p.Glu105Lys	missense_variant	2/7	ENST00000424542.7
NHERF2	NM_004785.6 linkuse as main transcript	c.313G>A	p.Glu105Lys	missense_variant	2/7
NHERF2	XM_047434923.1 linkuse as main transcript	c.313G>A	p.Glu105Lys	missense_variant	2/7
NHERF2	XM_047434924.1 linkuse as main transcript	c.-6G>A		5_prime_UTR_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHERF2	ENST00000424542.7 linkuse as main transcript	c.313G>A	p.Glu105Lys	missense_variant	2/7	1	NM_001130012.3	P1	Q15599-1
NHERF2	ENST00000432365.6 linkuse as main transcript	c.313G>A	p.Glu105Lys	missense_variant	2/7	1			Q15599-2
NHERF2	ENST00000567504.5 linkuse as main transcript	c.286G>A	p.Glu96Lys	missense_variant	2/3	3
NHERF2	ENST00000563587.5 linkuse as main transcript	c.-6G>A		5_prime_UTR_variant	1/6	2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000355

AC:

AN:

168940

Hom.:

AF XY:

0.0000332

AC XY:

AN XY:

90300

show subpopulations

Gnomad AFR exome

AF:

0.000220

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000856

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000290

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000184

AC:

AN:

1410742

Hom.:

Cov.:

AF XY:

0.0000129

AC XY:

AN XY:

697018

show subpopulations

Gnomad4 AFR exome

AF:

0.0000621

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000626

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000175

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000650

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000243

AC:

ExAC

AF:

0.0000174

AC:

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

Nov 08, 2022

The c.313G>A (p.E105K) alteration is located in exon 2 (coding exon 2) of the SLC9A3R2 gene. This alteration results from a G to A substitution at nucleotide position 313, causing the glutamic acid (E) at amino acid position 105 to be replaced by a lysine (K). 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

0.22

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.12

Cadd

Uncertain

Dann

Uncertain

1.0

Eigen

Benign

0.16

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.077

MetaRNN

Benign

0.22

T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.9

N;N;N

Sift

Benign

0.096

T;T;T

Sift4G

Uncertain

0.047

D;T;T

Polyphen

0.99

.;D;.

Vest4

0.54, 0.61

MVP

0.90

MPC

0.20

ClinPred

0.10

GERP RS

3.8

Varity_R

0.12

gMVP

0.43

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