16-2029711-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001130012.3(NHERF2):c.343G>C(p.Ala115Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.019 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NHERF2 NM_001130012.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.75

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08394036).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHERF2	NM_001130012.3	c.343G>C	p.Ala115Pro	missense_variant	2/7	ENST00000424542.7
NHERF2	NM_004785.6	c.343G>C	p.Ala115Pro	missense_variant	2/7
NHERF2	XM_047434923.1	c.343G>C	p.Ala115Pro	missense_variant	2/7
NHERF2	XM_047434924.1	c.25G>C	p.Ala9Pro	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHERF2	ENST00000424542.7	c.343G>C	p.Ala115Pro	missense_variant	2/7	1	NM_001130012.3	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 191 AN: 146062 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.000914

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00115

Gnomad ASJ AF: 0.000887

Gnomad EAS AF: 0.00377

Gnomad SAS AF: 0.00475

Gnomad FIN AF: 0.00268

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.00147

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0186 AC: 11199 AN: 602524 Hom.: 0 Cov.: 31 AF XY: 0.0166 AC XY: 5203 AN XY: 313026

Gnomad4 AFR exome AF: 0.0168

Gnomad4 AMR exome AF: 0.00259

Gnomad4 ASJ exome AF: 0.0103

Gnomad4 EAS exome AF: 0.0133

Gnomad4 SAS exome AF: 0.00320

Gnomad4 FIN exome AF: 0.00297

Gnomad4 NFE exome AF: 0.0242

Gnomad4 OTH exome AF: 0.0161

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00129 AC: 189 AN: 146182 Hom.: 0 Cov.: 32 AF XY: 0.00146 AC XY: 104 AN XY: 71084

Gnomad4 AFR AF: 0.000887

Gnomad4 AMR AF: 0.00115

Gnomad4 ASJ AF: 0.000887

Gnomad4 EAS AF: 0.00378

Gnomad4 SAS AF: 0.00450

Gnomad4 FIN AF: 0.00268

Gnomad4 NFE AF: 0.00103

Gnomad4 OTH AF: 0.00146

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

Jul 06, 2021

The c.343G>C (p.A115P) alteration is located in exon 2 (coding exon 2) of the SLC9A3R2 gene. This alteration results from a G to C substitution at nucleotide position 343, causing the alanine (A) at amino acid position 115 to be replaced by a proline (P). 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	0.060
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	0.75
Dann	Benign	0.56
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.63	T;T;T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.084	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.19	N;N;N;N
Sift	Benign	0.14	T;T;T;D
Sift4G	Uncertain	0.047	D;T;T;T
Polyphen		0.0	.;B;.;.
Vest4		0.15, 0.20, 0.18
MutPred		0.37		.;Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);.;
MVP		0.61
MPC		0.059
ClinPred		0.038	T
GERP RS		-1.4
Varity_R		0.031
gMVP		0.25

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: rs373924925; hg19: chr16-2079712;