16-2036468-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001130012.3(NHERF2):c.559C>T(p.Arg187Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00352 in 1,601,318 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (16 hom.)
• Consequence: NHERF2 NM_001130012.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.179

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008509934).
• BP6: Variant 16-2036468-C-T is Benign according to our data. Variant chr16-2036468-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2645965.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 384 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHERF2	NM_001130012.3	c.559C>T	p.Arg187Cys	missense_variant	3/7	ENST00000424542.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHERF2	ENST00000424542.7	c.559C>T	p.Arg187Cys	missense_variant	3/7	1	NM_001130012.3	P1

Frequencies

GnomAD3 genomes AF: 0.00252 AC: 384 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00410

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00254 AC: 569 AN: 223876 Hom.: 3 AF XY: 0.00273 AC XY: 334 AN XY: 122528

Gnomad AFR exome AF: 0.000871

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00233

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000495

Gnomad FIN exome AF: 0.000469

Gnomad NFE exome AF: 0.00441

Gnomad OTH exome AF: 0.00432

GnomAD4 exome AF: 0.00362 AC: 5246 AN: 1448978 Hom.: 16 Cov.: 32 AF XY: 0.00357 AC XY: 2567 AN XY: 719892

Gnomad4 AFR exome AF: 0.000693

Gnomad4 AMR exome AF: 0.00175

Gnomad4 ASJ exome AF: 0.00271

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000296

Gnomad4 FIN exome AF: 0.000469

Gnomad4 NFE exome AF: 0.00432

Gnomad4 OTH exome AF: 0.00323

GnomAD4 genome AF: 0.00251 AC: 383 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.00239 AC XY: 178 AN XY: 74488

Gnomad4 AFR AF: 0.000697

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00410

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00352 Hom.: 2

Bravo AF: 0.00292

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000988 AC: 4

ESP6500EA AF: 0.00492 AC: 41

ExAC AF: 0.00255 AC: 307

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

NHERF2: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.;.;T;.
Eigen	Benign	0.095
Eigen_PC	Benign	-0.069
FATHMM_MKL	Benign	0.091	N
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.0085	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.4	M;M;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D
REVEL	Benign	0.17
Sift	Benign	0.053	T;T;T;T;T
Sift4G	Uncertain	0.048	D;D;D;D;D
Polyphen		0.98	D;.;.;.;.
Vest4		0.29
MVP		0.65
MPC		0.31
ClinPred		0.022	T
GERP RS		3.6
Varity_R		0.34
gMVP		0.28

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: rs62038800; hg19: chr16-2086469;