16-2029778-A-G

Position:

• chr16-2029778-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001130012.3(NHERF2):​c.410A>G​(p.Lys137Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NHERF2 NM_001130012.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.108389884).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NHERF2	NM_001130012.3	c.410A>G	p.Lys137Arg	missense_variant	2/7	ENST00000424542.7	NP_001123484.1
NHERF2	NM_004785.6	c.410A>G	p.Lys137Arg	missense_variant	2/7		NP_004776.3
NHERF2	XM_047434923.1	c.410A>G	p.Lys137Arg	missense_variant	2/7		XP_047290879.1
NHERF2	XM_047434924.1	c.92A>G	p.Lys31Arg	missense_variant	2/7		XP_047290880.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NHERF2	ENST00000424542.7	c.410A>G	p.Lys137Arg	missense_variant	2/7	1	NM_001130012.3	ENSP00000408005.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 33

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

Oct 21, 2024

The c.410A>G (p.K137R) alteration is located in exon 2 (coding exon 2) of the SLC9A3R2 gene. This alteration results from a A to G substitution at nucleotide position 410, causing the lysine (K) at amino acid position 137 to be replaced by an arginine (R). 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	0.061
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Benign	0.82
DEOGEN2	Benign	0.059	.;T;.;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.57	T;T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	.;N;N;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.84	N;N;N;N
REVEL	Benign	0.028
Sift	Benign	0.13	T;T;T;T
Sift4G	Benign	0.29	T;T;T;T
Polyphen		0.0	.;B;.;.
Vest4		0.16, 0.099, 0.13
MutPred		0.24		.;Loss of ubiquitination at K137 (P = 0.0019);Loss of ubiquitination at K137 (P = 0.0019);.;
MVP		0.86
MPC		0.043
ClinPred		0.052	T
GERP RS		2.5
Varity_R		0.019
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-2079779; COSMIC: COSV99076528; COSMIC: COSV99076528;