16-2036480-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001130012.3(NHERF2):c.571C>G(p.Arg191Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000818 in 1,596,964 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.00056 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00085 (1 hom.)
• Consequence: NHERF2 NM_001130012.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.359

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=0.064713836).
• BS2: High AC in GnomAd at 85 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHERF2	NM_001130012.3	c.571C>G	p.Arg191Gly	missense_variant	3/7	ENST00000424542.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHERF2	ENST00000424542.7	c.571C>G	p.Arg191Gly	missense_variant	3/7	1	NM_001130012.3	P1

Frequencies

GnomAD3 genomes AF: 0.000558 AC: 85 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000506 AC: 109 AN: 215234 Hom.: 0 AF XY: 0.000365 AC XY: 43 AN XY: 117796

Gnomad AFR exome AF: 0.000421

Gnomad AMR exome AF: 0.000127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000216

Gnomad NFE exome AF: 0.000989

Gnomad OTH exome AF: 0.000369

GnomAD4 exome AF: 0.000845 AC: 1221 AN: 1444622 Hom.: 1 Cov.: 32 AF XY: 0.000778 AC XY: 558 AN XY: 717338

Gnomad4 AFR exome AF: 0.0000906

Gnomad4 AMR exome AF: 0.000117

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000238

Gnomad4 FIN exome AF: 0.000354

Gnomad4 NFE exome AF: 0.00104

Gnomad4 OTH exome AF: 0.000637

GnomAD4 genome AF: 0.000558 AC: 85 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.000591 AC XY: 44 AN XY: 74496

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000508 Hom.: 0

Bravo AF: 0.000672

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000251 AC: 1

ESP6500EA AF: 0.00121 AC: 10

ExAC AF: 0.000468 AC: 56

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2022

The c.571C>G (p.R191G) alteration is located in exon 3 (coding exon 3) of the SLC9A3R2 gene. This alteration results from a C to G substitution at nucleotide position 571, causing the arginine (R) at amino acid position 191 to be replaced by a glycine (G). 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	0.27
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.25	T;.;.;T;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.19	N
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.065	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Pathogenic	2.9	M;M;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-5.4	D;D;D;D;D
REVEL	Benign	0.086
Sift	Benign	0.035	D;D;D;D;D
Sift4G	Uncertain	0.038	D;D;T;D;D
Polyphen		0.84	P;.;.;.;.
Vest4		0.57
MVP		0.51
MPC		0.32
ClinPred		0.11	T
GERP RS		1.5
Varity_R		0.91
gMVP		0.54

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: rs200865634; hg19: chr16-2086481;